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George C. Prendergast – 1st expert 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, George C. Prendergast, Kevther Hoxha, 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.

Daitoku Sakamuro – 2nd expert 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.

Erica K Cassimere – 3rd expert 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.