The Experts below are selected from a list of 2928 Experts worldwide ranked by ideXlab platform

George C. Prendergast - One of the best experts on this subject based on the ideXlab platform.

  • 15 Role of immunohistochemical loss of BIN1/amphiphysin2 in prostatic carcinoma
    Molecular Pathology Colorectal Carcinoma and Prostate Carcinoma, 2020
    Co-Authors: James B Duhadaway, George C. Prendergast
    Abstract:

    Publisher Summary This chapter describes role of immunohistochemicai loss of BIN1/amphiphysin2 in prostatic carcinoma. In the prostate, BIN1 proteins are expressed robustly in the nucleus of normal cells, but they are often absent or mislocalized in cases of primary prostate adenocarcinoma and invariably absent in metastases. In vitro investigations with prostate-cancer cell lines show that ectopic expression of BIN1 proteins block proliferation and/or stimulate programmed cell death. Immunohistochemical analysis of BIN1 may have utility in discriminating the stage or prognosis of prostate cancers. The BIN1 gene encodes several alternately spliced adapter proteins that have been implicated in both vesicle dynamics and nuclear processes. There is considerable evidence that nuclear-localized BIN1 proteins have tumor suppressor and proapoptotic activities in cancer cells. Further, immunohistochemical analysis of BIN1 in prostate cancer may develop its potential as a prognostic marker or identifier for metastatic capacity.

  • BIN1 antibody lowers the expression of phosphorylated Tau in Alzheimer's disease.
    Journal of Cellular Biochemistry, 2019
    Co-Authors: Sunil Thomas, Kevther Hoxha, Allison Tran, George C. Prendergast
    Abstract:

    : Alzheimer's disease (AD) is an irreversible, progressive brain disorder responsible for memory loss leading to the inability to carry out the simplest tasks. AD is one of the leading causes of death in the United States. As yet there are no effective medications to treat this debilitating disease. In recent years, a human gene called bridging integrator 1 (BIN1) has emerged as one of the most important genes in affecting the incidence of sporadic AD. BIN1 can directly bind to Tau and mediates late onset AD risk by modulating Tau pathology. Recently our group found BIN1 antibody could exert drug-like properties in an animal model of ulcerative colitis. We hypothesized that the BIN1 monoclonal antibody (mAb) could be used in the treatment of AD by lowering the levels of Tau in cell culture and animal models. Cell culture studies confirmed that the BIN1 mAb (99D) could lower the levels of phosphorylated Tau (pTau). Multiple mechanisms aided by endosomal proteins and Fc gamma receptors are involved in the uptake of BIN1 mAb into cells. In Tau expressing cell culture, the BIN1 mAb induces the proteasome machinery leading to ubiquitination of molecules thereby preventing cell stress. In vivo studies demonstrated that treatment of P301S mice expressing Tau with the BIN1 mAb survived longer than the untreated mice. Our data confirm that BIN1 mAb lowers the levels of pTau and could be a drug candidate in the treatment of AD.

  • intestinal barrier tightening by a cell penetrating antibody to BIN1 a candidate target for immunotherapy of ulcerative colitis
    Journal of Cellular Biochemistry, 2019
    Co-Authors: Sunil Thomas, Kevther Hoxha, George C. Prendergast, Walker Alexander, John Gilligan, Rima Dilbarova, Kelly Whittaker, Andrew V Kossenkov, James M Mullin
    Abstract:

    : Patients afflicted with ulcerative colitis (UC) are at increased risk of colorectal cancer. While its causes are not fully understood, UC is associated with defects in colonic epithelial barriers that sustain inflammation of the colon mucosa caused by recruitment of lymphocytes and neutrophils into the lamina propria. Based on genetic evidence that attenuation of the bridging integrator 1 (BIN1) gene can limit UC pathogenicity in animals, we have explored BIN1 targeting as a therapeutic option. Early feasibility studies in the dextran sodium sulfate mouse model of experimental colitis showed that administration of a cell-penetrating BIN1 monoclonal antibody (BIN1 mAb 99D) could prevent lesion formation in the colon mucosa in part by preventing rupture of lymphoid follicles. In vivo administration of BIN1 mAb altered tight junction protein expression and cecal barrier function. Strikingly, electrophysiology studies in organ cultures showed that BIN1 mAb could elevate resistance and lower 14 C-mannitol leakage across the cecal mucosa, consistent with a direct strengthening of colonic barrier function. Transcriptomic analyses of colitis tissues highlighted altered expression of genes involved in circadian rhythm, lipid metabolism, and inflammation, with a correction of the alterations by BIN1 mAb treatment to patterns characteristic of normal tissues. Overall, our results suggest that BIN1 mAb protects against UC by directly improving colonic epithelial barrier function to limit gene expression and cytokine programs associated with colonic inflammation.

  • cardiac specific disruption of BIN1 in mice enables a model of stress and age associated dilated cardiomyopathy
    Journal of Cellular Biochemistry, 2015
    Co-Authors: Lisa Laurykleintop, Alexander J Muller, Jennifer Mulgrew, Ido Heletz, Radu Alexandru Nedelcoviciu, Mee Young Chang, David M Harris, Walter J Koch, Michael D Schneider, George C. Prendergast
    Abstract:

    Non-compensated dilated cardiomyopathy (DCM) leading to death from heart failure is rising rapidly in developed countries due to aging demographics, and there is a need for informative preclinical models to guide the development of effective therapeutic strategies to prevent or delay disease onset. In this study, we describe a novel model of heart failure based on cardiac-specific deletion of the prototypical mammalian BAR adapter-encoding gene BIN1, a modifier of age-associated disease. BIN1 deletion during embryonic development causes hypertrophic cardiomyopathy and neonatal lethality, but there is little information on how BIN1 affects cardiac function in adult animals. Here we report that cardiomyocyte-specific loss of BIN1 causes age-associated dilated cardiomyopathy (DCM) beginning by 8–10 months of age. Echocardiographic analysis showed that BIN1 loss caused a 45% reduction in ejection fraction during aging. Younger animals rapidly developed DCM if cardiac pressure overload was created by transverse aortic constriction. Heterozygotes exhibited an intermediate phenotype indicating BIN1 is haplo-insufficient to sustain normal heart function. BIN1 loss increased left ventricle (LV) volume and diameter during aging, but it did not alter LV volume or diameter in hearts from heterozygous mice nor did it affect LV mass. BIN1 loss increased interstitial fibrosis and mislocalization of the voltage-dependent calcium channel Cav1.2, and the lipid raft scaffold protein caveolin-3, which normally complexes with BIN1 and Cav1.2 in cardiomyocyte membranes. Our findings show how cardiac deficiency in BIN1 function causes age- and stress-associated heart failure, and they establish a new preclinical model of this terminal cardiac disease. J. Cell. Biochem. 116: 2541–2551, 2015. © 2015 Wiley Periodicals, Inc.

  • Cardiac‐Specific Disruption of BIN1 in Mice Enables a Model of Stress‐ and Age‐Associated Dilated Cardiomyopathy
    Journal of Cellular Biochemistry, 2015
    Co-Authors: Lisa Laury-kleintop, Alexander J Muller, Jennifer Mulgrew, Ido Heletz, Radu Alexandru Nedelcoviciu, Mee Young Chang, David M Harris, Walter J Koch, Michael D Schneider, George C. Prendergast
    Abstract:

    Non-compensated dilated cardiomyopathy (DCM) leading to death from heart failure is rising rapidly in developed countries due to aging demographics, and there is a need for informative preclinical models to guide the development of effective therapeutic strategies to prevent or delay disease onset. In this study, we describe a novel model of heart failure based on cardiac-specific deletion of the prototypical mammalian BAR adapter-encoding gene BIN1, a modifier of age-associated disease. BIN1 deletion during embryonic development causes hypertrophic cardiomyopathy and neonatal lethality, but there is little information on how BIN1 affects cardiac function in adult animals. Here we report that cardiomyocyte-specific loss of BIN1 causes age-associated dilated cardiomyopathy (DCM) beginning by 8–10 months of age. Echocardiographic analysis showed that BIN1 loss caused a 45% reduction in ejection fraction during aging. Younger animals rapidly developed DCM if cardiac pressure overload was created by transverse aortic constriction. Heterozygotes exhibited an intermediate phenotype indicating BIN1 is haplo-insufficient to sustain normal heart function. BIN1 loss increased left ventricle (LV) volume and diameter during aging, but it did not alter LV volume or diameter in hearts from heterozygous mice nor did it affect LV mass. BIN1 loss increased interstitial fibrosis and mislocalization of the voltage-dependent calcium channel Cav1.2, and the lipid raft scaffold protein caveolin-3, which normally complexes with BIN1 and Cav1.2 in cardiomyocyte membranes. Our findings show how cardiac deficiency in BIN1 function causes age- and stress-associated heart failure, and they establish a new preclinical model of this terminal cardiac disease. J. Cell. Biochem. 116: 2541–2551, 2015. © 2015 Wiley Periodicals, Inc.

Daitoku Sakamuro - One of the best experts on this subject based on the ideXlab platform.

  • Abstract C297: PARP1 and BIN1 cooperate to act as a novel co-repressor for E2F1.
    Molecular Cancer Therapeutics, 2020
    Co-Authors: Alpana Kumari, Slovenie Pyndiah, Erica K Cassimere, Daitoku Sakamuro
    Abstract:

    Background: Bridging integrator 1 (BIN1) is a transcriptional co-repressor and inhibits oncogenic activities of c-MYC and E1A oncoproteins1. BIN1 inhibits c-MYC through direct interaction, whereas the mechanism by which BIN1 attenuates the oncogenic transformation mediated by adenovirus E1A remains elusive. Since BIN1 does not physically interact with E1A, we hypothesized that BIN1 diminishes a cellular effector, which can be activated by E1A and is essential for E1A transformation. One of the well-recognized cellular effectors for E1A transformation is the E2F1 transcription factor. Although retinoblastoma (RB) protein is an authentic E2F1 inhibitor, loss of RB does not immediately result in cancer development, suggesting that an anti-E2F1 function, which is independent of RB, compensates for RB deficiency. BIN1 was recently shown to interact with poly (ADP-ribose) polymerase1 (PARP1), a component of transcriptional complex2. Given that PARP1 also interacts with E2F1, we hypothesized functional cross talk between BIN1 and PARP1 to curb E2F1 activity. Experimental Procedures: E2F1 activity was determined using an adenovirus-driven E2F1-sensitive luciferase reporter vector, E2A-Luc. Protein-protein interaction was studied by co-immunoprecipitation followed by Western blot analysis. Chromatin immunoprecipitation assay was used to demonstrate protein-DNA interaction. Colony formation and foci formation assays were performed to investigate BIN1-mediated tumor suppression in the presence and absence of PARP1. Results: We discovered that BIN1 physically interacts with E2F1 and inhibits its transactivation. Interestingly, depletion of PARP1 released endogenous E2F1 activity, regardless of the status of RB expression. Furthermore, BIN1 failed to inhibit E2F1 activity in the absence of PARP1, but RB does not need PARP1 to inhibit E2F1 activity. Chromatin immunoprecipitation assays suggested that BIN1 and PARP1 co-existed on an E2F-responsive promoter. Moreover, in the absence of PARP1, the binding affinities of both BIN1 and E2F1 to the promoter were significantly reduced. In addition, only in the presence of PARP1, ectopically expressed BIN1 inhibited tumor colony formation and HPV16 E7 oncoprotein-dependent cellular transformation. Our results suggest that BIN1 and PARP1 cooperate to inhibit E2F1 activity and suppress oncogenic transformation. Conclusion: We conclude that BIN1 is a novel E2F1 corepressor in cooperation with PARP1. BIN1-PARP1 interaction may serve as a safety device to control deregulated E2F1 activity due to RB loss. This study was supported by NIH R01CA140379 (to D.S.). Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C297. Citation Format: Alpana Kumari, Slovenie Pyndiah, Erica K. Cassimere, Daitoku Sakamuro. PARP1 and BIN1 cooperate to act as a novel co-repressor for E2F1. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C297.

  • loss of the tumor suppressor BIN1 enables atm ser thr kinase activation by the nuclear protein e2f1 and renders cancer cells resistant to cisplatin
    Journal of Biological Chemistry, 2019
    Co-Authors: Watson P Folk, Alpana Kumari, Tetsushi Iwasaki, Slovenie Pyndiah, Joanna C Johnson, Erica K Cassimere, Amy L Abduloviccui, Daitoku Sakamuro
    Abstract:

    : The tumor suppressor bridging integrator 1 (BIN1) is a corepressor of the transcription factor E2F1 and inhibits cell-cycle progression. BIN1 also curbs cellular poly(ADP-ribosyl)ation (PARylation) and increases sensitivity of cancer cells to DNA-damaging therapeutic agents such as cisplatin. However, how BIN1 deficiency, a hallmark of advanced cancer cells, increases cisplatin resistance remains elusive. Here, we report that BIN1 inactivates ataxia telangiectasia-mutated (ATM) serine/threonine kinase, particularly when BIN1 binds E2F1. BIN1 + 12A (a cancer-associated BIN1 splicing variant) also inhibited cellular PARylation, but only BIN1 increased cisplatin sensitivity. BIN1 prevented E2F1 from transcriptionally activating the human ATM promoter, whereas BIN1 + 12A did not physically interact with E2F1. Conversely, BIN1 loss significantly increased E2F1-dependent formation of MRE11A/RAD50/NBS1 DNA end-binding protein complex and efficiently promoted ATM autophosphorylation. Even in the absence of dsDNA breaks (DSBs), BIN1 loss promoted ATM-dependent phosphorylation of histone H2A family member X (forming γH2AX, a DSB biomarker) and mediator of DNA damage checkpoint 1 (MDC1, a γH2AX-binding adaptor protein for DSB repair). Of note, even in the presence of transcriptionally active (i.e. proapoptotic) TP53 tumor suppressor, BIN1 loss generally increased cisplatin resistance, which was conversely alleviated by ATM inactivation or E2F1 reduction. However, E2F2 or E2F3 depletion did not recapitulate the cisplatin sensitivity elicited by E2F1 elimination. Our study unveils an E2F1-specific signaling circuit that constitutively activates ATM and provokes cisplatin resistance in BIN1-deficient cancer cells and further reveals that γH2AX emergence may not always reflect DSBs if BIN1 is absent.

  • Loss of the tumor suppressor BIN1 enables ATM Ser/Thr kinase activation by the nuclear protein E2F1 and renders cancer cells resistant to cisplatin
    Journal of Biological Chemistry, 2019
    Co-Authors: Watson P Folk, Alpana Kumari, Tetsushi Iwasaki, Slovenie Pyndiah, Joanna C Johnson, Erica K Cassimere, Amy L. Abdulovic-cui, Daitoku Sakamuro
    Abstract:

    : The tumor suppressor bridging integrator 1 (BIN1) is a corepressor of the transcription factor E2F1 and inhibits cell-cycle progression. BIN1 also curbs cellular poly(ADP-ribosyl)ation (PARylation) and increases sensitivity of cancer cells to DNA-damaging therapeutic agents such as cisplatin. However, how BIN1 deficiency, a hallmark of advanced cancer cells, increases cisplatin resistance remains elusive. Here, we report that BIN1 inactivates ataxia telangiectasia-mutated (ATM) serine/threonine kinase, particularly when BIN1 binds E2F1. BIN1 + 12A (a cancer-associated BIN1 splicing variant) also inhibited cellular PARylation, but only BIN1 increased cisplatin sensitivity. BIN1 prevented E2F1 from transcriptionally activating the human ATM promoter, whereas BIN1 + 12A did not physically interact with E2F1. Conversely, BIN1 loss significantly increased E2F1-dependent formation of MRE11A/RAD50/NBS1 DNA end-binding protein complex and efficiently promoted ATM autophosphorylation. Even in the absence of dsDNA breaks (DSBs), BIN1 loss promoted ATM-dependent phosphorylation of histone H2A family member X (forming γH2AX, a DSB biomarker) and mediator of DNA damage checkpoint 1 (MDC1, a γH2AX-binding adaptor protein for DSB repair). Of note, even in the presence of transcriptionally active (i.e. proapoptotic) TP53 tumor suppressor, BIN1 loss generally increased cisplatin resistance, which was conversely alleviated by ATM inactivation or E2F1 reduction. However, E2F2 or E2F3 depletion did not recapitulate the cisplatin sensitivity elicited by E2F1 elimination. Our study unveils an E2F1-specific signaling circuit that constitutively activates ATM and provokes cisplatin resistance in BIN1-deficient cancer cells and further reveals that γH2AX emergence may not always reflect DSBs if BIN1 is absent.

  • Abstract B03: Physical and functional interactions between two tumor suppressors, BIN1 and RB1
    Molecular Cancer Research, 2016
    Co-Authors: Watson P Folk, Alpana Kumari, Erica K Cassimere, Joanna K. Johnson, Daitoku Sakamuro
    Abstract:

    The bridging integrator 1 (BIN1) protein was originally identified as a cellular adaptor protein that interacts with the transcription factor c-MYC and inhibits cell proliferation. However, BIN1 inhibits tumor cell growth by both a BIN1 MYC-binding domain (MBD)-dependent mechanism and an MBD-independent mechanism. Consistently, BIN1 promotes skeletal muscle differentiation in vitro where c-MYC is not detectable, suggesting that an undefined BIN1-interacting protein other than c-MYC determines BIN1-mediated growth arrest in an MYC-independent manner. Here we show the functional interplay between BIN1 and the RB1 tumor suppressor for growth arrest. BIN1 interacts with RB1 in differentiated (i.e. growth-arrested) C2C12 skeletal myotube cells, whereas such interaction was largely reduced in undifferentiated (i.e. actively proliferating) C2C12 myoblast cells. Acting through the coiled-coil BAR domain, an essential effector region for BIN1-mediated growth suppression, BIN1 physically interacts with the C pocket domain of RB1 in vitro and in vivo . The RB1-BIN1 protein-protein interaction is functionally germane. First, adenovirus E1A viral oncoprotein, which is known to stimulate cell proliferation in rodent fibroblast model systems by interacting with RB1, disrupted the RB1-BIN1 interaction in vitro . Second, the cancer suppression mediated by overexpressed BIN1 was partly attenuated by the co-transfection of short-hairpin RNA against RB1. Third, an MBD-independent BIN1-associated transcriptional corepressor activity was attenuated when endogenous RB1 was silenced. Fourth, serum stimulation-dependent phosphorylation of the RB-C pocket domain at serine 807/811, critical phosphorylation sites for RB1 inactivation by cyclin-dependent kinases 4 and 6 (CDK4/6), was largely reduced in BIN1-proficient cells. Conversely, the effect of PD-0332991, a chemical inhibitor of CDK4/6, on the growth suppression of RB-proficient cancer cells was more profound in BIN1-deficient cancer cells. Collectively, these data suggest that BIN1 and RB1 physically interact with one another and cooperate to induce growth arrest during cellular differentiation and cancer suppression. Citation Format: Watson P. Folk, Alpana Kumari, Erica Cassimere, Joanna Johnson, Daitoku Sakamuro. Physical and functional interactions between two tumor suppressors, BIN1 and RB1. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B03.

  • identification of a novel effector domain of BIN1 for cancer suppression
    Journal of Cellular Biochemistry, 2011
    Co-Authors: Greta L Lundgaard, Slovenie Pyndiah, Erica K Cassimere, Natae E Daniels, Kazi Mokim Ahmed, Amelie Rodrigue, Daisuke Kihara, Carol Beth Post, Daitoku Sakamuro
    Abstract:

    Bridging integrator 1 (BIN1) is a nucleocytoplasmic adaptor protein with tumor suppressor properties. The protein interacts with and inhibits the c-MYC transcription factor through the BIN1 MYC-binding domain (MBD). However, in vitro colony formation assays have clearly demonstrated that the MBD is not essential for BIN1-mediated growth arrest. We hypothesized that BIN1 contains a MYC-independent effector domain (MID) for cancer suppression. Because a functionally unique domain frequently contains a distinct structure, the human fulllength BIN1 protein was subjected to limited trypsin digestion and the digested peptides were analyzed with Edman sequencing and mass spectrometry. We identified a trypsin-resistant peptide that corresponds to amino acids 146–268 of BIN1. It encompassed part of the BAR region, a putative effector region of BIN1. Computational analysis predicted that the peptide is very likely to exhibit coiled-coil motifs, implying a potential role for this region in sustaining the BIN1 structure and function. Like MBD-deleted BIN1, the trypsin-resistant peptide of BIN1 was predominantly present in the cytoplasm and was sufficient to inhibit cancer growth, regardless of dysregulated c-MYC activity. Our results suggest that the coiled-coil BIN1 BAR peptide encodes a novel BIN1 MID domain, through which BIN1 acts as a MYC-independent cancer suppressor. J. Cell. Biochem. 112: 2992–3001, 2011. 2011 Wiley-Liss, Inc.

Erica K Cassimere - One of the best experts on this subject based on the ideXlab platform.

  • Abstract C297: PARP1 and BIN1 cooperate to act as a novel co-repressor for E2F1.
    Molecular Cancer Therapeutics, 2020
    Co-Authors: Alpana Kumari, Slovenie Pyndiah, Erica K Cassimere, Daitoku Sakamuro
    Abstract:

    Background: Bridging integrator 1 (BIN1) is a transcriptional co-repressor and inhibits oncogenic activities of c-MYC and E1A oncoproteins1. BIN1 inhibits c-MYC through direct interaction, whereas the mechanism by which BIN1 attenuates the oncogenic transformation mediated by adenovirus E1A remains elusive. Since BIN1 does not physically interact with E1A, we hypothesized that BIN1 diminishes a cellular effector, which can be activated by E1A and is essential for E1A transformation. One of the well-recognized cellular effectors for E1A transformation is the E2F1 transcription factor. Although retinoblastoma (RB) protein is an authentic E2F1 inhibitor, loss of RB does not immediately result in cancer development, suggesting that an anti-E2F1 function, which is independent of RB, compensates for RB deficiency. BIN1 was recently shown to interact with poly (ADP-ribose) polymerase1 (PARP1), a component of transcriptional complex2. Given that PARP1 also interacts with E2F1, we hypothesized functional cross talk between BIN1 and PARP1 to curb E2F1 activity. Experimental Procedures: E2F1 activity was determined using an adenovirus-driven E2F1-sensitive luciferase reporter vector, E2A-Luc. Protein-protein interaction was studied by co-immunoprecipitation followed by Western blot analysis. Chromatin immunoprecipitation assay was used to demonstrate protein-DNA interaction. Colony formation and foci formation assays were performed to investigate BIN1-mediated tumor suppression in the presence and absence of PARP1. Results: We discovered that BIN1 physically interacts with E2F1 and inhibits its transactivation. Interestingly, depletion of PARP1 released endogenous E2F1 activity, regardless of the status of RB expression. Furthermore, BIN1 failed to inhibit E2F1 activity in the absence of PARP1, but RB does not need PARP1 to inhibit E2F1 activity. Chromatin immunoprecipitation assays suggested that BIN1 and PARP1 co-existed on an E2F-responsive promoter. Moreover, in the absence of PARP1, the binding affinities of both BIN1 and E2F1 to the promoter were significantly reduced. In addition, only in the presence of PARP1, ectopically expressed BIN1 inhibited tumor colony formation and HPV16 E7 oncoprotein-dependent cellular transformation. Our results suggest that BIN1 and PARP1 cooperate to inhibit E2F1 activity and suppress oncogenic transformation. Conclusion: We conclude that BIN1 is a novel E2F1 corepressor in cooperation with PARP1. BIN1-PARP1 interaction may serve as a safety device to control deregulated E2F1 activity due to RB loss. This study was supported by NIH R01CA140379 (to D.S.). Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C297. Citation Format: Alpana Kumari, Slovenie Pyndiah, Erica K. Cassimere, Daitoku Sakamuro. PARP1 and BIN1 cooperate to act as a novel co-repressor for E2F1. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C297.

  • loss of the tumor suppressor BIN1 enables atm ser thr kinase activation by the nuclear protein e2f1 and renders cancer cells resistant to cisplatin
    Journal of Biological Chemistry, 2019
    Co-Authors: Watson P Folk, Alpana Kumari, Tetsushi Iwasaki, Slovenie Pyndiah, Joanna C Johnson, Erica K Cassimere, Amy L Abduloviccui, Daitoku Sakamuro
    Abstract:

    : The tumor suppressor bridging integrator 1 (BIN1) is a corepressor of the transcription factor E2F1 and inhibits cell-cycle progression. BIN1 also curbs cellular poly(ADP-ribosyl)ation (PARylation) and increases sensitivity of cancer cells to DNA-damaging therapeutic agents such as cisplatin. However, how BIN1 deficiency, a hallmark of advanced cancer cells, increases cisplatin resistance remains elusive. Here, we report that BIN1 inactivates ataxia telangiectasia-mutated (ATM) serine/threonine kinase, particularly when BIN1 binds E2F1. BIN1 + 12A (a cancer-associated BIN1 splicing variant) also inhibited cellular PARylation, but only BIN1 increased cisplatin sensitivity. BIN1 prevented E2F1 from transcriptionally activating the human ATM promoter, whereas BIN1 + 12A did not physically interact with E2F1. Conversely, BIN1 loss significantly increased E2F1-dependent formation of MRE11A/RAD50/NBS1 DNA end-binding protein complex and efficiently promoted ATM autophosphorylation. Even in the absence of dsDNA breaks (DSBs), BIN1 loss promoted ATM-dependent phosphorylation of histone H2A family member X (forming γH2AX, a DSB biomarker) and mediator of DNA damage checkpoint 1 (MDC1, a γH2AX-binding adaptor protein for DSB repair). Of note, even in the presence of transcriptionally active (i.e. proapoptotic) TP53 tumor suppressor, BIN1 loss generally increased cisplatin resistance, which was conversely alleviated by ATM inactivation or E2F1 reduction. However, E2F2 or E2F3 depletion did not recapitulate the cisplatin sensitivity elicited by E2F1 elimination. Our study unveils an E2F1-specific signaling circuit that constitutively activates ATM and provokes cisplatin resistance in BIN1-deficient cancer cells and further reveals that γH2AX emergence may not always reflect DSBs if BIN1 is absent.

  • Loss of the tumor suppressor BIN1 enables ATM Ser/Thr kinase activation by the nuclear protein E2F1 and renders cancer cells resistant to cisplatin
    Journal of Biological Chemistry, 2019
    Co-Authors: Watson P Folk, Alpana Kumari, Tetsushi Iwasaki, Slovenie Pyndiah, Joanna C Johnson, Erica K Cassimere, Amy L. Abdulovic-cui, Daitoku Sakamuro
    Abstract:

    : The tumor suppressor bridging integrator 1 (BIN1) is a corepressor of the transcription factor E2F1 and inhibits cell-cycle progression. BIN1 also curbs cellular poly(ADP-ribosyl)ation (PARylation) and increases sensitivity of cancer cells to DNA-damaging therapeutic agents such as cisplatin. However, how BIN1 deficiency, a hallmark of advanced cancer cells, increases cisplatin resistance remains elusive. Here, we report that BIN1 inactivates ataxia telangiectasia-mutated (ATM) serine/threonine kinase, particularly when BIN1 binds E2F1. BIN1 + 12A (a cancer-associated BIN1 splicing variant) also inhibited cellular PARylation, but only BIN1 increased cisplatin sensitivity. BIN1 prevented E2F1 from transcriptionally activating the human ATM promoter, whereas BIN1 + 12A did not physically interact with E2F1. Conversely, BIN1 loss significantly increased E2F1-dependent formation of MRE11A/RAD50/NBS1 DNA end-binding protein complex and efficiently promoted ATM autophosphorylation. Even in the absence of dsDNA breaks (DSBs), BIN1 loss promoted ATM-dependent phosphorylation of histone H2A family member X (forming γH2AX, a DSB biomarker) and mediator of DNA damage checkpoint 1 (MDC1, a γH2AX-binding adaptor protein for DSB repair). Of note, even in the presence of transcriptionally active (i.e. proapoptotic) TP53 tumor suppressor, BIN1 loss generally increased cisplatin resistance, which was conversely alleviated by ATM inactivation or E2F1 reduction. However, E2F2 or E2F3 depletion did not recapitulate the cisplatin sensitivity elicited by E2F1 elimination. Our study unveils an E2F1-specific signaling circuit that constitutively activates ATM and provokes cisplatin resistance in BIN1-deficient cancer cells and further reveals that γH2AX emergence may not always reflect DSBs if BIN1 is absent.

  • Abstract B03: Physical and functional interactions between two tumor suppressors, BIN1 and RB1
    Molecular Cancer Research, 2016
    Co-Authors: Watson P Folk, Alpana Kumari, Erica K Cassimere, Joanna K. Johnson, Daitoku Sakamuro
    Abstract:

    The bridging integrator 1 (BIN1) protein was originally identified as a cellular adaptor protein that interacts with the transcription factor c-MYC and inhibits cell proliferation. However, BIN1 inhibits tumor cell growth by both a BIN1 MYC-binding domain (MBD)-dependent mechanism and an MBD-independent mechanism. Consistently, BIN1 promotes skeletal muscle differentiation in vitro where c-MYC is not detectable, suggesting that an undefined BIN1-interacting protein other than c-MYC determines BIN1-mediated growth arrest in an MYC-independent manner. Here we show the functional interplay between BIN1 and the RB1 tumor suppressor for growth arrest. BIN1 interacts with RB1 in differentiated (i.e. growth-arrested) C2C12 skeletal myotube cells, whereas such interaction was largely reduced in undifferentiated (i.e. actively proliferating) C2C12 myoblast cells. Acting through the coiled-coil BAR domain, an essential effector region for BIN1-mediated growth suppression, BIN1 physically interacts with the C pocket domain of RB1 in vitro and in vivo . The RB1-BIN1 protein-protein interaction is functionally germane. First, adenovirus E1A viral oncoprotein, which is known to stimulate cell proliferation in rodent fibroblast model systems by interacting with RB1, disrupted the RB1-BIN1 interaction in vitro . Second, the cancer suppression mediated by overexpressed BIN1 was partly attenuated by the co-transfection of short-hairpin RNA against RB1. Third, an MBD-independent BIN1-associated transcriptional corepressor activity was attenuated when endogenous RB1 was silenced. Fourth, serum stimulation-dependent phosphorylation of the RB-C pocket domain at serine 807/811, critical phosphorylation sites for RB1 inactivation by cyclin-dependent kinases 4 and 6 (CDK4/6), was largely reduced in BIN1-proficient cells. Conversely, the effect of PD-0332991, a chemical inhibitor of CDK4/6, on the growth suppression of RB-proficient cancer cells was more profound in BIN1-deficient cancer cells. Collectively, these data suggest that BIN1 and RB1 physically interact with one another and cooperate to induce growth arrest during cellular differentiation and cancer suppression. Citation Format: Watson P. Folk, Alpana Kumari, Erica Cassimere, Joanna Johnson, Daitoku Sakamuro. Physical and functional interactions between two tumor suppressors, BIN1 and RB1. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B03.

  • identification of a novel effector domain of BIN1 for cancer suppression
    Journal of Cellular Biochemistry, 2011
    Co-Authors: Greta L Lundgaard, Slovenie Pyndiah, Erica K Cassimere, Natae E Daniels, Kazi Mokim Ahmed, Amelie Rodrigue, Daisuke Kihara, Carol Beth Post, Daitoku Sakamuro
    Abstract:

    Bridging integrator 1 (BIN1) is a nucleocytoplasmic adaptor protein with tumor suppressor properties. The protein interacts with and inhibits the c-MYC transcription factor through the BIN1 MYC-binding domain (MBD). However, in vitro colony formation assays have clearly demonstrated that the MBD is not essential for BIN1-mediated growth arrest. We hypothesized that BIN1 contains a MYC-independent effector domain (MID) for cancer suppression. Because a functionally unique domain frequently contains a distinct structure, the human fulllength BIN1 protein was subjected to limited trypsin digestion and the digested peptides were analyzed with Edman sequencing and mass spectrometry. We identified a trypsin-resistant peptide that corresponds to amino acids 146–268 of BIN1. It encompassed part of the BAR region, a putative effector region of BIN1. Computational analysis predicted that the peptide is very likely to exhibit coiled-coil motifs, implying a potential role for this region in sustaining the BIN1 structure and function. Like MBD-deleted BIN1, the trypsin-resistant peptide of BIN1 was predominantly present in the cytoplasm and was sufficient to inhibit cancer growth, regardless of dysregulated c-MYC activity. Our results suggest that the coiled-coil BIN1 BAR peptide encodes a novel BIN1 MID domain, through which BIN1 acts as a MYC-independent cancer suppressor. J. Cell. Biochem. 112: 2992–3001, 2011. 2011 Wiley-Liss, Inc.

Pierre De Rossi - One of the best experts on this subject based on the ideXlab platform.

  • neuronal BIN1 regulates presynaptic neurotransmitter release and memory consolidation
    Cell Reports, 2020
    Co-Authors: Pierre De Rossi, Robert J Andrew, Timothy F Musial, Toshihiro Nomura, Nicolas Y Masse, Vandana Sampathkumar, Ari Sudwarts, Aleksandra J Recupero, Thomas Le Metayer
    Abstract:

    Summary BIN1, a member of the BAR adaptor protein family, is a significant late-onset Alzheimer disease risk factor. Here, we investigate BIN1 function in the brain using conditional knockout (cKO) models. Loss of neuronal BIN1 expression results in the select impairment of spatial learning and memory. Examination of hippocampal CA1 excitatory synapses reveals a deficit in presynaptic release probability and slower depletion of neurotransmitters during repetitive stimulation, suggesting altered vesicle dynamics in BIN1 cKO mice. Super-resolution and immunoelectron microscopy localizes BIN1 to presynaptic sites in excitatory synapses. BIN1 cKO significantly reduces synapse density and alters presynaptic active zone protein cluster formation. Finally, 3D electron microscopy reconstruction analysis uncovers a significant increase in docked and reserve pools of synaptic vesicles at hippocampal synapses in BIN1 cKO mice. Our results demonstrate a non-redundant role for BIN1 in presynaptic regulation, thus providing significant insights into the fundamental function of BIN1 in synaptic physiology relevant to Alzheimer disease.

  • alzheimer s disease gwas risk factor BIN1 regulates presynaptic neurotransmitter release and memory consolidation
    2019
    Co-Authors: Pierre De Rossi, Robert J Andrew, Timothy F Musial, Toshihiro Nomura, Nicolas Y Masse, Vandana Sampathkumar, Ari Sudwarts, Aleksandra J Recupero, Thomas Le Metayer, Mitchell T Hansen
    Abstract:

    BIN1, a member of the BAR adaptor protein family, is a significant late-onset Alzheimer’s disease risk factor. Here, we investigated BIN1 function in the brain using conditional knockout (cKO) models. The loss of neuronal BIN1 expression resulted in select impairment of spatial learning and memory. Examination of hippocampal CA1 excitatory synapses revealed a deficit in presynaptic release probability and slower depletion of neurotransmitter during repetitive stimulation, suggesting altered vesicle dynamics in BIN1 cKO mice. Super-resolution and immunoelectron microscopy localized BIN1 to presynaptic sites in excitatory synapses. BIN1 cKO significantly reduced synapse density and altered presynaptic active zone protein cluster formation. Finally, 3D-electron microscopy reconstruction analysis uncovered a significant increase of docked and reserve pool of synaptic vesicles at hippocampal synapses in BIN1 cKO mice. Our results demonstrate a non-redundant role for BIN1 in presynaptic regulation, thus providing novel insights into BIN1's fundamental function in synaptic physiology relevant to Alzheimer’s disease.

  • aberrant accrual of BIN1 near alzheimer s disease amyloid deposits in transgenic models
    Brain Pathology, 2019
    Co-Authors: Pierre De Rossi, Robert J Andrew, Timothy F Musial, Virginie Buggiaprevot, Guilian Xu, Moorthi Ponnusamy, Han Ly, Sofia V Krause, Richard C Rice, Valentine De Lestoile
    Abstract:

    : Bridging integrator 1 (BIN1) is the most significant late-onset Alzheimer's disease (AD) susceptibility locus identified via genome-wide association studies. BIN1 is an adaptor protein that regulates membrane dynamics in the context of endocytosis and membrane remodeling. An increase in BIN1 expression and changes in the relative levels of alternatively spliced BIN1 isoforms have been reported in the brains of patients with AD. BIN1 can bind to Tau, and an increase in BIN1 expression correlates with Tau pathology. In contrast, the loss of BIN1 expression in cultured cells elevates Aβ production and Tau propagation by insfluencing endocytosis and recycling. Here, we show that BIN1 accumulates adjacent to amyloid deposits in vivo. We found an increase in insoluble BIN1 and a striking accrual of BIN1 within and near amyloid deposits in the brains of multiple transgenic models of AD. The peri-deposit aberrant BIN1 localization was conspicuously different from the accumulation of APP and BACE1 within dystrophic neurites. Although BIN1 is highly expressed in mature oligodendrocytes, BIN1 association with amyloid deposits occurred in the absence of the accretion of other oligodendrocyte or myelin proteins. Finally, super-resolution microscopy and immunogold electron microscopy analyses highlight the presence of BIN1 in proximity to amyloid fibrils at the edges of amyloid deposits. These results reveal the aberrant accumulation of BIN1 is a feature associated with AD amyloid pathology. Our findings suggest a potential role for BIN1 in extracellular Aβ deposition in vivo that is distinct from its well-characterized function as an adaptor protein in endocytosis and membrane remodeling.

  • reduction of the expression of the late onset alzheimer s disease ad risk factor BIN1 does not affect amyloid pathology in an ad mouse model
    Journal of Biological Chemistry, 2019
    Co-Authors: Robert J Andrew, Pierre De Rossi, Sofia V Krause, Richard C Rice, Aleksandra J Recupero, Lisa Laurykleintop, Phuong Nguyen, Haley R Kowalski, Thomas Guerbette, Steven L Wagner
    Abstract:

    : Alzheimer's disease (AD) is pathologically characterized by the deposition of the β-amyloid (Aβ) peptide in senile plaques in the brain, leading to neuronal dysfunction and eventual decline in cognitive function. Genome-wide association studies have identified the bridging integrator 1 (BIN1) gene within the second most significant susceptibility locus for late-onset AD. BIN1 is a member of the amphiphysin family of proteins and has reported roles in the generation of membrane curvature and endocytosis. Endocytic dysfunction is a pathological feature of AD, and endocytosis of the amyloid precursor protein is an important step in its subsequent cleavage by β-secretase (BACE1). In vitro evidence implicates BIN1 in endosomal sorting of BACE1 and Aβ generation in neurons, but a role for BIN1 in this process in vivo is yet to be described. Here, using biochemical and immunohistochemistry analyses we report that a 50% global reduction of BIN1 protein levels resulting from a single BIN1 allele deletion in mice does not change BACE1 levels or localization in vivo, nor does this reduction alter the production of endogenous murine Aβ in nontransgenic mice. Furthermore, we found that reduction of BIN1 levels in the 5XFAD mouse model of amyloidosis does not alter Aβ deposition nor behavioral deficits associated with cerebral amyloid burden. Finally, a conditional BIN1 knockout in excitatory neurons did not alter BACE1, APP, C-terminal fragments derived from BACE1 cleavage of APP, or endogenous Aβ levels. These results indicate that BIN1 function does not regulate Aβ generation in vivo.

  • Aberrant accrual of BIN1 near Alzheimer’s disease amyloid deposits in transgenic models
    Brain Pathology, 2018
    Co-Authors: Pierre De Rossi, Robert J Andrew, Timothy F Musial, Guilian Xu, Moorthi Ponnusamy, Han Ly, Sofia V Krause, Richard C Rice, Virginie Buggia-prévot, Valentine De L’estoile
    Abstract:

    : Bridging integrator 1 (BIN1) is the most significant late-onset Alzheimer's disease (AD) susceptibility locus identified via genome-wide association studies. BIN1 is an adaptor protein that regulates membrane dynamics in the context of endocytosis and membrane remodeling. An increase in BIN1 expression and changes in the relative levels of alternatively spliced BIN1 isoforms have been reported in the brains of patients with AD. BIN1 can bind to Tau, and an increase in BIN1 expression correlates with Tau pathology. In contrast, the loss of BIN1 expression in cultured cells elevates Aβ production and Tau propagation by insfluencing endocytosis and recycling. Here, we show that BIN1 accumulates adjacent to amyloid deposits in vivo. We found an increase in insoluble BIN1 and a striking accrual of BIN1 within and near amyloid deposits in the brains of multiple transgenic models of AD. The peri-deposit aberrant BIN1 localization was conspicuously different from the accumulation of APP and BACE1 within dystrophic neurites. Although BIN1 is highly expressed in mature oligodendrocytes, BIN1 association with amyloid deposits occurred in the absence of the accretion of other oligodendrocyte or myelin proteins. Finally, super-resolution microscopy and immunogold electron microscopy analyses highlight the presence of BIN1 in proximity to amyloid fibrils at the edges of amyloid deposits. These results reveal the aberrant accumulation of BIN1 is a feature associated with AD amyloid pathology. Our findings suggest a potential role for BIN1 in extracellular Aβ deposition in vivo that is distinct from its well-characterized function as an adaptor protein in endocytosis and membrane remodeling.

Julien Chapuis - One of the best experts on this subject based on the ideXlab platform.

  • BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr^348 phosphorylation
    Acta Neuropathologica, 2019
    Co-Authors: Maxime Sartori, Tiago Mendes, Shruti Desai, Alessia Lasorsa, Adrien Herledan, Nicolas Malmanche, Petra Mäkinen, Mikael Marttinen, Idir Malki, Julien Chapuis
    Abstract:

    The bridging integrator 1 gene ( BIN1 ) is a major genetic risk factor for Alzheimer’s disease (AD). In this report, we investigated how BIN1-dependent pathophysiological processes might be associated with Tau. We first generated a cohort of control and transgenic mice either overexpressing human MAPT (Tg MAPT ) or both human MAPT and BIN1 (Tg MAPT ;Tg BIN1 ), which we followed-up from 3 to 15 months. In Tg MAPT ;Tg BIN1 mice short-term memory deficits appeared earlier than in Tg MAPT mice; however—unlike Tg MAPT mice—Tg MAPT ;Tg BIN1 mice did not exhibit any long-term or spatial memory deficits for at least 15 months. After killing the cohort at 18 months, immunohistochemistry revealed that BIN1 overexpression prevents both Tau mislocalization and somatic inclusion in the hippocampus, where an increase in BIN1–Tau interaction was also observed. We then sought mechanisms controlling the BIN1–Tau interaction. We developed a high-content screening approach to characterize modulators of the BIN1–Tau interaction in an agnostic way (1,126 compounds targeting multiple pathways), and we identified—among others—an inhibitor of calcineurin, a Ser/Thr phosphatase. We determined that calcineurin dephosphorylates BIN1 on a cyclin-dependent kinase phosphorylation site at T348, promoting the open conformation of the neuronal BIN1 isoform. Phosphorylation of this site increases the availability of the BIN1 SH3 domain for Tau interaction, as demonstrated by nuclear magnetic resonance experiments and in primary neurons. Finally, we observed that although the levels of the neuronal BIN1 isoform were unchanged in AD brains, phospho-BIN1(T348):BIN1 ratio was increased, suggesting a compensatory mechanism. In conclusion, our data support the idea that BIN1 modulates the AD risk through an intricate regulation of its interaction with Tau. Alteration in BIN1 expression or activity may disrupt this regulatory balance with Tau and have direct effects on learning and memory.

  • BIN1 recovers tauopathy induced long term memory deficits in mice and interacts with tau through thr348 phosphorylation
    bioRxiv, 2018
    Co-Authors: Maxime Sartori, Tiago Mendes, Shruti Desai, Alessia Lasorsa, Nicolas Malmanche, Petra Mäkinen, Mikael Marttinen, Idir Malki, Adrien Herldean, Julien Chapuis
    Abstract:

    The bridging integrator 1 gene (BIN1) is a major genetic risk factor for Alzheimer disease (AD). In this report, we investigated how BIN1-dependent pathophysiological processes might be associated with Tau. We first generated a cohort of control and transgenic mice either overexpressing human MAPT (TgMAPT) or both human MAPT and BIN1 (TgMAPT;TgBIN1), which we followed-up from 3 to 15 months. In TgMAPT;TgBIN1 mice short-term memory deficits appeared earlier than in TgMAPT mice; however, unlike TgMAPT mice, TgMAPT;TgBIN1 mice did not exhibit any long-term or spatial memory deficits for at least 15 months. After sacrifice of the cohort at 18 months, immunohistochemistry revealed that BIN1 overexpression prevents both Tau mislocalization and somatic inclusion in the hippocampus, where an increase in BIN1-Tau interaction was also observed. We then sought mechanisms controlling the BIN1-Tau interaction. We developed a high-content screening approach to characterize modulators of the BIN1-Tau interaction in an agnostic way (1,126 compounds targeting multiple pathways), and we identified, among others, an inhibitor of Calcineurin, a Ser/Thr phosphatase. We determined that Calcineurin dephosphorylates a Cyclin-dependent kinase phosphorylation site at T348 that shifts the dynamic equilibrium of the open/closed conformation of the neuronal BIN1 isoform towards the open form. Phosphorylation of this site increases the availability of the BIN1 SH3 domain for Tau interaction, as demonstrated by nuclear magnetic resonance experiments and in primary neurons. Finally, we observed that the levels of the neuronal BIN1 isoform were decreased in AD brains, whereas phospho-BIN1(T348):BIN1 ratio was increased, suggesting a compensatory mechanism. In conclusion, our data support the idea that BIN1 modulates the AD risk through an intricate regulation of its interaction with Tau. Any increase in BIN1 expression or activity may disrupt this regulatory balance with Tau and have direct effects on learning and memory.

  • increased expression of BIN1 mediates alzheimer genetic risk by modulating tau pathology
    Molecular Psychiatry, 2013
    Co-Authors: Julien Chapuis, Yoann Sottejeau, Franck Hansmannel, Marc Gistelinck, Anais Mounier, C Van Cauwenberghe, Kristof Van Kolen, F Geller, Denise Harold, Pierre Dourlen
    Abstract:

    Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer’s disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ~28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14–1.26) (P=3.8 × 10−11)). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.