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Yi Sun - One of the best experts on this subject based on the ideXlab platform.
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Tumor Suppressor FBXW7 and Its Regulation of DNA Damage Response and Repair
'Frontiers Media SA', 2021Co-Authors: Yi Sun, Huiyin LanAbstract:The proper DNA damage response (DDR) and repair are the central molecular mechanisms for the maintenance of cellular homeostasis and genomic integrity. The abnormality in this process is frequently observed in human cancers, and is an important contributing factor to cancer development. FBXW7 is an F-box protein serving as the substrate recognition component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase. By selectively targeting many oncoproteins for proteasome-mediated degradation, FBXW7 acts as a typical tumor suppressor. Recent studies have demonstrated that FBXW7 also plays critical roles in the process of DDR and repair. In this review, we first briefly introduce the processes of protein ubiquitylation by SCFFBXW7 and DDR/repair, then provide an overview of the molecular characteristics of FBXW7. We next discuss how FBXW7 regulates the process of DDR and repair, and its translational implication. Finally, we propose few future perspectives to further elucidate the role of FBXW7 in regulation of a variety of biological processes and tumorigenesis, and to design a number of approaches for FBXW7 reactivation in a subset of human cancers for potential anticancer therapy
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the fbxw2 msx2 sox2 axis regulates stem cell property and drug resistance of cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Yuan Yin, Chuanming Xie, Mingjia Tan, Guoan Chen, Rachel Schiff, Xiufang Xiong, Yi SunAbstract:SOX2 is a key transcription factor that plays critical roles in maintaining stem cell property and conferring drug resistance. However, the underlying mechanisms by which SOX2 level is precisely regulated remain elusive. Here we report that MLN4924, also known as pevonedistat, a small-molecule inhibitor of neddylation currently in phase II clinical trials, down-regulates SOX2 expression via causing accumulation of MSX2, a known transcription repressor of SOX2 expression. Mechanistic characterization revealed that MSX2 is a substrate of FBXW2 E3 ligase. FBXW2 binds to MSX2 and promotes MSX2 ubiquitylation and degradation. Likewise, FBXW2 overexpression shortens the protein half-life of MSX2, whereas FBXW2 knockdown extends it. We further identified hypoxia as a stress condition that induces VRK2 kinase to facilitate MSX2-FBXW2 binding and FBXW2-mediated MSX2 ubiquitylation and degradation, leading to SOX2 induction via derepression. Biologically, expression of FBXW2 or SOX2 promotes tumor sphere formation, which is blocked by MSX2 expression. By down-regulating SOX2 through inactivation of FBXW2 E3 ligase, MLN4924 sensitizes breast cancer cells to tamoxifen in both in vitro and in vivo cancer cell models. Thus, a negative cascade of the FBXW2-MSX2-SOX2 axis was established, which regulates stem cell property and drug resistance. Finally, an inverse correlation of expression was found between FBXW2 and MSX2 in lung and breast cancer tissues. Collectively, our study revealed an anticancer mechanism of MLN4924. By inactivating FBXW2, MLN4924 caused MSX2 accumulation to repress SOX2 expression, leading to suppression of stem cell property and sensitization of breast cancer cells to tamoxifen.
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fbxw2 suppresses migration and invasion of lung cancer cells via promoting β catenin ubiquitylation and degradation
Nature Communications, 2019Co-Authors: Mingjia Tan, Xiufang Xiong, Yi Sun, Fei YangAbstract:FBXW2 inhibits proliferation of lung cancer cells by targeting SKP2 for degradation. Whether and how FBXW2 regulates tumor invasion and metastasis is previously unknown. Here, we report that FBXW2 is an E3 ligase for β-catenin. FBXW2 binds to β-catenin upon EGF-AKT1-mediated phosphorylation on Ser552, and promotes its ubiquitylation and degradation. FBXW2 overexpression reduces β-catenin levels and protein half-life, whereas FBXW2 knockdown increases β-catenin levels, protein half-life and transcriptional activity. Functionally, FBXW2 overexpression inhibits migration and invasion by blocking transactivation of MMPs driven by β-catenin, whereas FXBW2 knockdown promotes migration, invasion and metastasis both in vitro and in vivo lung cancer models. In human lung cancer specimens, while FBXW2 levels are inversely correlated with β-catenin levels and lymph-node metastasis, lower FBXW2 coupled with higher β-catenin, predict a worse patient survival. Collectively, our study demonstrates that FBXW2 inhibits tumor migration, invasion and metastasis in lung cancer cells by targeting β-catenin for degradation.
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the FBXW7 shoc2 raptor axis controls the cross talks between the ras erk and mtorc1 signaling pathways
Cell Reports, 2019Co-Authors: Chuanming Xie, Mingjia Tan, Xiufang Xiong, Yi Sun, Xiao-tong Lin, Yihan Jiang, Ye TanAbstract:FBXW7 is a tumor suppressive E3 ligase, whereas RAS-ERK and mechanistic target of rapamycin kinase (mTORC1) are two major oncogenic pathways. Whether and how FBXW7 regulates these two oncogenic pathways are unknown. Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. FBXW7-mediated SHOC2 degradation terminates the RAS-MAPK signals and inhibits proliferation. Furthermore, SHOC2 selectively binds to Raptor to competitively inhibit the Raptor-mTOR binding to inactivate mTORC1 and induce autophagy, whereas Raptor binding of SHOC2 inhibits the SHOC2-RAS binding to block the MAPK pathway and proliferation. Finally, SHOC2 is overexpressed in pancreatic cancer, which correlated with poor patient survival. SHOC2 mutations were found in lung cancer tissues with gain-of-function activity. Collectively, the SHOC2-Raptor interaction triggers negative cross-talk between RAS-ERK and mTORC1 pathways, whereas FBXW7 regulates both pathways by targeting SHOC2 for ubiquitylation and degradation.
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The FBXW7-SHOC2-Raptor Axis Controls the Cross-Talks between the RAS-ERK and mTORC1 Signaling Pathways
'Elsevier BV', 2019Co-Authors: Chuanming Xie, Mingjia Tan, Xiufang Xiong, Xiao-tong Lin, Yihan Jiang, Ye Tan, Yi SunAbstract:Summary: FBXW7 is a tumor suppressive E3 ligase, whereas RAS-ERK and mechanistic target of rapamycin kinase (mTORC1) are two major oncogenic pathways. Whether and how FBXW7 regulates these two oncogenic pathways are unknown. Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. FBXW7-mediated SHOC2 degradation terminates the RAS-MAPK signals and inhibits proliferation. Furthermore, SHOC2 selectively binds to Raptor to competitively inhibit the Raptor-mTOR binding to inactivate mTORC1 and induce autophagy, whereas Raptor binding of SHOC2 inhibits the SHOC2-RAS binding to block the MAPK pathway and proliferation. Finally, SHOC2 is overexpressed in pancreatic cancer, which correlated with poor patient survival. SHOC2 mutations were found in lung cancer tissues with gain-of-function activity. Collectively, the SHOC2-Raptor interaction triggers negative cross-talk between RAS-ERK and mTORC1 pathways, whereas FBXW7 regulates both pathways by targeting SHOC2 for ubiquitylation and degradation. : In this study, Xie et al. show upon growth stimulation that RAS-MAPK is activated to phosphorylate SHOC2 on T507 to facilitate its binding with FBXW7β for ubiquitylation and degradation, thus establishing a negative feedback loop. Furthermore, the SHOC2-RAPTOR interaction can inactivate either pathway to keep proliferation and autophagy under precise control. Keywords: autophagy, cell proliferation, FBXW7, MAPK, mTOR, Raptor, RAS-RAF-ERK, SCF E3 ligase, SHOC2, ubiquitylation and degradatio
Keiichi I Nakayama - One of the best experts on this subject based on the ideXlab platform.
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degradation of the endoplasmic reticulum anchored transcription factor myrf by the ubiquitin ligase scfFBXW7 in a manner dependent on the kinase gsk 3
Journal of Biological Chemistry, 2018Co-Authors: Shogo Nakayama, Kanae Yumimoto, Atsuki Kawamura, Keiichi I NakayamaAbstract:The ubiquitin-proteasome system regulates the abundance of many cellular proteins by mediating their targeted degradation. We previously developed a method—differential proteomics–based identification of ubiquitylation substrates (DiPIUS)—for the comprehensive identification of substrates for a given F-box protein subunit of SCF-type ubiquitin ligases. We have now applied DiPIUS to the F-box protein FBXW7 in three cell lines (mHepa, Neuro2A, and C2C12) and thereby identified myelin regulatory factor (MyRF), an endoplasmic reticulum–anchored transcription factor that is essential for myelination of nerves in the central nervous system, as a candidate substrate of FBXW7 specifically in mHepa cells. Co-immunoprecipitation analysis confirmed that the NH2-terminal cytoplasmic domain of MyRF interacted with FBXW7 in these cells. Furthermore, an in vitro ubiquitylation assay revealed that MyRF undergoes polyubiquitylation in the presence of purified recombinant SCFFBXW7. In addition, the stability of MyRF in mHepa cells was increased by mutation of a putative phosphodegron sequence or by exposure of the cells to an inhibitor of glycogen synthase kinase-3 (GSK-3). We found that MyRF mRNA is not restricted to the central nervous system but is instead distributed widely among mouse tissues. Furthermore, with the use of RNA sequencing in mHepa cells overexpressing or depleted of MyRF, we identified many novel potential target genes of MyRF. Our results thus suggest that FBXW7 controls the transcription of MyRF target genes in various tissues through regulation of MyRF protein stability in a manner dependent on MyRF phosphorylation by GSK-3.
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regulation of gata binding protein 2 levels via ubiquitin dependent degradation by fbw7 involvement of cyclin b cyclin dependent kinase 1 mediated phosphorylation of thr176 in gata binding protein 2
Journal of Biological Chemistry, 2015Co-Authors: Tomomi Nakajima, Keiichi I Nakayama, Kanae Yumimoto, Kyoko Kitagawa, Tatsuya Ohhata, Satoshi Sakai, Chiharu Uchida, Kiyoshi Shibata, Naoko Minegishi, Kazuma MasumotoAbstract:A GATA family transcription factor, GATA-binding protein 2 (GATA2), participates in cell growth and differentiation of various cells, such as hematopoietic stem cells. Although its expression level is controlled by transcriptional induction and proteolytic degradation, the responsible E3 ligase has not been identified. Here, we demonstrate that F-box/WD repeat-containing protein 7 (Fbw7/FBXW7), a component of Skp1, Cullin 1, F-box-containing complex (SCF)-type E3 ligase, is an E3 ligase for GATA2. GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr176. Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr176, was cyclin B-cyclin-dependent kinase 1 (CDK1). Moreover, depletion of endogenous Fbw7 stabilized endogenous GATA2 in K562 cells. Conditional Fbw7 depletion in mice increased GATA2 levels in hematopoietic stem cells and myeloid progenitors at the early stage. Increased GATA2 levels in Fbw7-conditional knock-out mice were correlated with a decrease in a c-Kit high expressing population of myeloid progenitor cells. Our results suggest that Fbw7 is a bona fide E3 ubiquitin ligase for GATA2 in vivo.
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f box protein FBXW7 inhibits cancer metastasis in a non cell autonomous manner
Journal of Clinical Investigation, 2015Co-Authors: Kanae Yumimoto, Ichiro Onoyama, Sayuri Akiyoshi, H Ueo, Yasuaki Sagara, Shinji Ohno, Masaki Mori, Koshi Mimori, Keiichi I NakayamaAbstract:The gene encoding F-box protein FBXW7 is frequently mutated in many human cancers. Although most previous studies have focused on the tumor-suppressive capacity of FBXW7 in tumor cells themselves, we determined that FBXW7 in the host microenvironment also suppresses cancer metastasis. Deletion of FBXW7 in murine BM-derived stromal cells induced accumulation of NOTCH and consequent transcriptional activation of Ccl2. FBXW7-deficient mice exhibited increased serum levels of the chemokine CCL2, which resulted in the recruitment of both monocytic myeloid-derived suppressor cells and macrophages, thereby promoting metastatic tumor growth. Administration of a CCL2 receptor antagonist blocked the enhancement of metastasis in FBXW7-deficient mice. Furthermore, in human breast cancer patients, FBXW7 expression in peripheral blood was associated with serum CCL2 concentration and disease prognosis. Together, these results suggest that FBXW7 antagonizes cancer development in not only a cell-autonomous manner, but also a non-cell-autonomous manner, and that modulation of the FBXW7/NOTCH/CCL2 axis may provide a potential approach to suppression of cancer metastasis.
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skp1 cullin f box scf type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self renewal
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Mito Kanatsushinohara, Keiichi I Nakayama, Ichiro Onoyama, Takashi ShinoharaAbstract:Spermatogonial stem cells (SSCs) undergo self-renewal divisions to support spermatogenesis throughout life. Although several positive regulators of SSC self-renewal have been discovered, little is known about the negative regulators. Here, we report that F-box and WD-40 domain protein 7 (FBXW7), a component of the Skp1-Cullin-F-box–type ubiquitin ligase, is a negative regulator of SSC self-renewal. FBXW7 is expressed in undifferentiated spermatogonia in a cell cycle-dependent manner. Although peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1), essential for spermatogenesis, is thought to destroy FBXW7, Pin1 depletion decreased FBXW7 expression. Spermatogonial transplantation showed that FBXW7 overexpression compromised SSC activity whereas FBXW7 deficiency enhanced SSC colonization and caused accumulation of undifferentiated spermatogonia, suggesting that the level of FBXW7 is critical for self-renewal and differentiation. Screening of putative FBXW7 targets revealed that FBXW7 deficiency up-regulated myelocytomatosis oncogene (MYC) and cyclin E1 (CCNE1). Although depletion of Myc/Mycn or Ccne1/Ccne2 compromised SSC activity, overexpression of Myc, but not Ccne1, increased colonization of SSCs. These results suggest that FBXW7 regulates SSC self-renewal in a negative manner by degradation of MYC.
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f box and wd repeat domain containing 7 FBXW7 protein targets endoplasmic reticulum anchored osteogenic and chondrogenic transcriptional factors for degradation
Journal of Biological Chemistry, 2013Co-Authors: Kanae Yumimoto, Ichiro Onoyama, Masaki Matsumoto, Kazunori Imaizumi, Keiichi I NakayamaAbstract:Abstract Although identification of substrates for an enzyme is a key step in elucidation of its biological functions, detection of the interaction between enzymes and substrates remains challenging. We recently developed a new approach, termed differential proteomics-based identification of ubiquitylation substrates (DiPIUS), for the discovery of substrates of ubiquitin ligases. We have now applied this approach to FBXW7, the F-box protein component of an Skp1-Cul1-F-box protein-type ubiquitin ligase and, thereby, identified two similar transcription factors, old astrocyte specifically induced substance (OASIS) and BBF2 human homolog on chromosome 7 (BBF2H7), as candidate substrates. Coimmunoprecipitation analysis confirmed that the α and γ isoforms of FBXW7 interact with OASIS and BBF2H7 in vivo. Sustained overexpression of FBXW7 resulted in marked down-regulation of OASIS and BBF2H7, whereas RNAi-mediated FBXW7 depletion stabilized both proteins. Mutation of a putative Cdc4 phosphodegron in OASIS and BBF2H7 attenuated their association with FBXW7 and resulted in their stabilization. Depletion of FBXW7 promoted the differentiation of mouse C2C12 mesenchymal cells into osteoblasts in association with the accumulation of OASIS. Conversely, overexpression of FBXW7 in C2C12 cells resulted in down-regulation of Col1A1 mRNA, a target of OASIS. Conditional ablation of FBXW7 in primary mouse mesenchymal cells promoted chondrogenesis in association with up-regulation of BBF2H7, whereas overexpression of FBXW7 inhibited chondrogenesis in ATDC5 cells. Collectively, our results suggest that OASIS and BBF2H7 are bona fide substrates of FBXW7 and that FBXW7 controls osteogenesis and chondrogenesis by targeting OASIS and BBF2H7, respectively, for degradation.
Ivo Leuschner - One of the best experts on this subject based on the ideXlab platform.
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subtype specific FBXW7 mutation and mycn copy number gain in wilms tumor
Clinical Cancer Research, 2010Co-Authors: Richard D Williams, Reem Alsaadi, Tasnim Chagtai, Sergey V Popov, Boo Messahel, N J Sebire, Manfred Gessler, Jenny Wegert, Norbert Graf, Ivo LeuschnerAbstract:Purpose: Wilms' tumor (WT), the most common pediatric renal malignancy, is associated with mutations in several well-characterized genes, most notably WT1, CTNNB1, WTX, and TP53. However, the majority of cases do not harbor mutations in these genes. We hypothesized that additional drivers of tumor behavior would be contained within areas of consistent genomic copy number change, especially those associated with the WT risk groups defined by the International Society of Paediatric Oncology (SIOP). Experimental Design: We analyzed high-resolution (Affymetrix 250K single nucleotide polymorphism array) genomic copy number profiles of over 100 tumors from selected risk groups treated under the SIOP protocols, further characterizing genes of interest by sequencing, Multiplex Ligation–dependent Probe Amplification, or fluorescence in situ hybridization. Results: We identified FBXW7, an E3 ubiquitin ligase component, as a novel Wilms' tumor gene, mutated or deleted in ∼4% of tumors examined. Strikingly, 3 of 14 (21%) of tumors with epithelial type histology after neoadjuvant chemotherapy had FBXW7 aberrations, whereas a fourth WT patient had germline mutations in both FBXW7 and WT1. We also showed that MYCN copy number gain, detected in 9 of 104 (8.7%) of cases, is relatively common in WT and significantly more so in tumors of the high risk diffuse anaplastic subtype (6 of 19, 32%). Conclusions: Because MYCN is itself a target of FBXW7-mediated ubiquitination and degradation, these results suggest that a common pathway is dysregulated by different mechanisms in various WT subtypes. Emerging therapies that target MYCN, which is amplified in several other pediatric cancers, may therefore be of value in high risk Wilms' tumor.
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subtype specific FBXW7 mutation and mycn copy number gain in wilms tumor
Clinical Cancer Research, 2010Co-Authors: Richard Williams, Reem Alsaadi, Tasnim Chagtai, Boo Messahel, N J Sebire, Manfred Gessler, Jenny Wegert, Norbert Graf, Sergey Popov, Ivo LeuschnerAbstract:Purpose: Wilms9 tumor (WT), the most common pediatric renal malignancy, is associated with mutations in several well-characterized genes, most notably WT1, CTNNB1, WTX , and TP53 . However, the majority of cases do not harbor mutations in these genes. We hypothesized that additional drivers of tumor behavior would be contained within areas of consistent genomic copy number change, especially those associated with the WT risk groups defined by the International Society of Paediatric Oncology (SIOP). Experimental Design: We analyzed high-resolution (Affymetrix 250K single nucleotide polymorphism array) genomic copy number profiles of over 100 tumors from selected risk groups treated under the SIOP protocols, further characterizing genes of interest by sequencing, Multiplex Ligation–dependent Probe Amplification, or fluorescence in situ hybridization. Results: We identified FBXW7 , an E3 ubiquitin ligase component, as a novel Wilms9 tumor gene, mutated or deleted in ∼4% of tumors examined. Strikingly, 3 of 14 (21%) of tumors with epithelial type histology after neoadjuvant chemotherapy had FBXW7 aberrations, whereas a fourth WT patient had germline mutations in both FBXW7 and WT1 . We also showed that MYCN copy number gain, detected in 9 of 104 (8.7%) of cases, is relatively common in WT and significantly more so in tumors of the high risk diffuse anaplastic subtype (6 of 19, 32%). Conclusions: Because MYCN is itself a target of FBXW7-mediated ubiquitination and degradation, these results suggest that a common pathway is dysregulated by different mechanisms in various WT subtypes. Emerging therapies that target MYCN, which is amplified in several other pediatric cancers, may therefore be of value in high risk Wilms9 tumor. Clin Cancer Res; 16(7); 2036–45. ©2010 AACR.
Fadlo R Khuri - One of the best experts on this subject based on the ideXlab platform.
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mtor complex 2 stabilizes mcl 1 protein by suppressing its glycogen synthase kinase 3 dependent and scf FBXW7 mediated degradation
Molecular and Cellular Biology, 2015Co-Authors: Xingming Deng, Fadlo R KhuriAbstract:mTOR complex 2 (mTORC2) regulates cell survival and growth through undefined mechanisms. Mcl-1, a Bcl-2 family protein, functions as an oncogenic protein. The connection between mTORC2 and Mcl-1 stability has not been established and was thus the focus of this study. Mcl-1 levels in cancer cells were decreased by mTOR kinase inhibitors (TORKinibs), which inhibit both mTORCs, by knocking down rictor and by knocking out rictor or Sin1 but not by silencing raptor. TORKinib treatment and rictor knockdown did not alter Mcl-1 mRNA levels but rather decreased its protein stability. Moreover, TORKinib-induced Mcl-1 reduction was rescued by proteasome inhibition. Consistently, TORKinib increased Mcl-1 ubiquitination. Hence, it is clear that inhibition of mTORC2 enhances Mcl-1 degradation, resulting in Mcl-1 reduction. Suppression of glycogen synthase kinase 3 (GSK3) or FBXW7 rescued Mcl-1 reduction induced by TORKinibs or rictor knockdown. Thus, mTORC2 inhibition apparently induces Mcl-1 degradation through a GSK3-dependent and SCF-FBXW7-mediated mechanism. Intriguingly, we detected a direct association between mTORC2 and SCF-FBXW7; this association could be inhibited by TORKinib treatment, suggesting that mTORC2 may directly associate with and inhibit the SCF-FBXW7 complex, resulting in delayed Mcl-1 degradation. Collectively, our findings highlight a novel mechanism by which mTORC2 regulates cell survival and growth by stabilizing Mcl-1.
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rictor undergoes glycogen synthase kinase 3 gsk3 dependent FBXW7 mediated ubiquitination and proteasomal degradation
Journal of Biological Chemistry, 2015Co-Authors: Junghui Koo, Zixu Mao, Fadlo R Khuri, Shiyong SunAbstract:Rictor, an essential component of mTOR complex 2 (mTORC2), plays a pivotal role in regulating mTOR signaling and other biological functions. Posttranslational regulation of rictor (e.g. via degradation) and its underlying mechanism are largely undefined and thus are the focus of this study. Chemical inhibition of the proteasome increased rictor ubiquitination and levels. Consistently, inhibition of FBXW7 with various genetic means including knockdown, knock-out, and enforced expression of a dominant-negative mutant inhibited rictor ubiquitination and increased rictor levels, whereas enforced expression of FBXW7 decreased rictor stability and levels. Moreover, we detected an interaction between FBXW7 and rictor. Hence, rictor is degraded through an FBXW7-mediated ubiquitination/proteasome mechanism. We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability. Finally, enforced activation of Akt enhanced rictor levels and increased mTORC2 activity as evidenced by increased formation of mTORC2 and elevated phosphorylation of Akt, SGK1, and PKCα. Hence we suggest that PI3K/Akt signaling may positively regulate mTORC2 signaling, likely through suppressing GSK3-dependent rictor degradation.
Heike Laman - One of the best experts on this subject based on the ideXlab platform.
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Analysis of the FBXO7 promoter reveals overlapping Pax5 and c-Myb binding sites functioning in B cells.
Biochemical and biophysical research communications, 2021Co-Authors: Rebecca B. Harris, Suzanne J. Randle, Heike LamanAbstract:Abstract Fbxo7 is a key player in the differentiation and function of numerous blood cell types, and in neurons, oligodendrocytes and spermatocytes. In an effort to gain insight into the physiological and pathological settings where Fbxo7 is likely to play a key role, we sought to define the transcription factors which direct FBXO7 expression. Using sequence alignments across 28 species, we defined the human FBXO7 promoter and found that it contains two conserved regions enriched for multiple transcription factor binding sites. Many of these have roles in either neuronal or haematopoietic development. Using various FBXO7 promoter reporters, we found ELF4, Pax5 and c-Myb have functional binding sites that activate transcription. We find endogenous Pax5 is bound to the FBXO7 promoter in pre-B cells, and that the exogenous expression of Pax5 represses Fbxo7 transcription in early pro-B cells.
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Analysis of the FBXO7 promoter reveals overlapping Pax5 and c-Myb binding sites functioning in B cells
2019Co-Authors: Suzanne J. Randle, Heike LamanAbstract:Abstract Fbxo7 is a key player in the differentiation and function of numerous blood cell types, and in neurons, oligodendrocytes and spermatocytes. In an effort to gain insight into the physiological and pathological settings where Fbxo7 is likely to play a key role, we sought to define the transcription factors which direct FBXO7 expression. Using sequence alignments across 28 species, we defined the human FBXO7 promoter and found that it contains two conserved regions enriched for multiple transcription factor binding sites. Many of these have roles in either neuronal or haematopoietic development. Using various FBXO7 promoter reporters, we found ELF4, Pax5 and c-Myb have functional binding sites that activate transcription. Overlap of Pax5 and c-Myb binding sites suggest that these factors bind cooperatively to transactivate the FBXO7 promoter. Although endogenous Pax5 is bound to the FBXO7 promoter in B cells, c-Myb is also required for FBXO7 expression. Our data suggest the interplay of multiple transcription factors regulate the FBXO7 promoter.
