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Srikumar Chellappan - One of the best experts on this subject based on the ideXlab platform.
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Prohibitin physically interacts with MCM proteins and inhibits mammalian DNA replication.
Cell cycle (Georgetown Tex.), 2009Co-Authors: Wasia Rizwani, Mark G. Alexandrow, Srikumar ChellappanAbstract:Prohibitin, a tumor suppressor protein, has been shown to repress E2F-mediated transcription and arrest cell cycle progression. while Prohibitin has been proposed to regulate cell cycle progression by repressing transcriptional targets of E2F1, it is not clear whether other mechanisms are also involved in mediating the growth arrest. Here we demonstrate that Prohibitin can function as a potent inhibitor of DNA replication by interacting with members of Minichromosome maintenance complex of proteins (MCM2-7). The data presented here indicates that Prohibitin can physically interact with MCM2, MCM5 and MCM7 in in vitro GST binding assays as well as in MCF-7 cells as seen by immunoprecipitation-western blot experiments. The association was cell cycle dependent, and more pronounced 4-8 hours after serum stimulation of quiescent cells. Prohibitin associated more robustly with MCM2 and MCM5 compared to MCM7, suggesting that Prohibitin mainly interacts with the regulatory subunits of the MCM complex. Confirming these results, Prohibitin was found to co-localize with MCM2, MCM5 and MCM7 in MCF-7 cells, as seen by double immunofluorescence experiments. Further, Prohibitin strongly inhibited DNA replication in an in vitro replication assay. These results strongly suggest that Prohibitin effectively represses replication by interacting with the components of mammalian replication machinery and this might contribute to the growth regulatory properties of Prohibitin.
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Prohibitin 2 physically interacts with E2F1 and represses transcription
Cancer Research, 2007Co-Authors: Smitha Pillai, Srikumar ChellappanAbstract:1241 The two strucurally related proteins Prohibitin 1 and Prohibitin 2 are involved in multiple cellular functions such as cell cycle regulation, transmembrane signal transduction and cellular senescence. Earlier studies from our lab had shown that Prohibitin 1, a potential tumor suppressor protein, binds to Rb and E2F transcription factors and represses E2F1-mediated trannscription via recruitment of transcriptional co-repressors such as N-CoR and histone deacetylase 1 (HDAC1). Prohibitin 2 (PHB2), also known as repressor of estrogen receptor activity (REA), shows extensive homology to Prohibitin 1 and has been shown to interact with and inhibit the transcriptional activity of estrogen receptor, MyoD and MEF2. We now present evidence that S-35 labeled Prohibitin 2 can physically interact with Rb and E2F1 in vitro as seen in GST-binding assays. Furthermore, this interaction was confirmed in vivo by immunoprecipitation-western blot analysis in MCF-7 breast cancer cells. Phb2 could also repress E2F1 mediated transcription in transient transfection assays in MCF-7 cells. Attempts were made to determine the region of Prohibitin 2 that is involved in transcriptional repression. Toward this purpose deletion mutants of Prohibitin 2 expressing amino acid residues 1-171, 170-299 and 226-299 were made. Transient transfection assays were conducted using an E2CAT reporter, which had an E2F1-responsive promoter element from the adenovirus E2 gene fused to a CAT gene. Cotransfection of E2F1 induced this promoter, while full length Prohibitin 2 as well as the Phb2 deletion mutant construct containing residues 170-299 effectively repressed E2F1 mediated transcription. However, the Prohibitin 2 construct that spanned residues 1-171 and 226-299 did not show transcriptional repression indicating that residues 170-226 are probably involved in transcriptional repression. These results indicate that Prohibitin 2 is a novel regulator of E2F1 function and might channel specific signaling cascades to the cell cycle regulatory machinery.
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Differential regulation of human YY1 and caspase 7 promoters by Prohibitin through E2F1 and p53 binding sites
The Biochemical journal, 2006Co-Authors: Bharat H. Joshi, Shipra Rastogi, M. Morris, L. M. Carastro, C. Decook, E. Seto, Srikumar ChellappanAbstract:Prohibitin is a 30 kDa growth suppressive protein that has pleiotropic functions in the cell. Although Prohibitin has been demonstrated to have potent transcriptional regulatory functions, it has also been proposed to facilitate protein folding in the mitochondria and promote cell migration in association with Raf-1. Our previous studies have shown that Prohibitin physically interacts with the marked-box domain of E2F family members and represses their transcriptional activity; in contrast, Prohibitin could bind to and enhance the transcriptional activity of p53. Here, we show that promoters of human YY1 (Yin and Yang 1) as well as caspase 7 genes are modulated by Prohibitin. YY1 promoter activity was reduced upon overexpression of Prohibitin, while it was enhanced when Prohibitin was depleted by small interfering RNA techniques. The repressive effects of Prohibitin on the YY1 promoter were mediated through E2F binding sites, as seen by mutational analysis and chromatin immunoprecipitation assays. Further, depletion of E2F1 prevented Prohibitin from repressing the YY1 promoter. In contrast with YY1, Prohibitin overexpression led to enhanced levels of caspase 7, whereas depletion of Prohibitin reduced it. Interestingly, the caspase 7 promoter was found to have p53-binding sites and Prohibitin activated this promoter through p53. These studies show that Prohibitin can have diverse effects on the expression of different genes and the activity of various cellular promoters is affected by Prohibitin. Further, it appears very likely that Prohibitin carries out many of its cellular functions by affecting the transcription of different genes.
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Prohibitin is a novel target gene of vitamin D involved in its antiproliferative action in breast cancer cells.
Cancer research, 2006Co-Authors: Xinjian Peng, Sheng Wang, Srikumar Chellappan, Rajeshwari R. Mehta, Rajendra G. MehtaAbstract:Previously, we showed that N-methyl-N-nitrosourea-transformed MCF12F breast epithelial cells exhibited differential expression of several genes, including up-regulation of Prohibitin and elevated sensitivity to a relatively noncalcemic vitamin D analogue, 1alpha-hydroxyvitamin D5 [1alpha(OH)D5]. In this report, we evaluated the functional significance of Prohibitin in relation to the cellular response to vitamin D. The in silico screening for putative transcription factor binding sites identified two vitamin D receptor (VDR)/retinoid X receptor binding sites in the 1-kb promoter region of Prohibitin. Prohibitin up-regulation by 1alpha(OH)D5 treatment at both transcriptional and translational levels was confirmed by real-time reverse transcription-PCR and Western blot analysis in breast cancer cells, identifying Prohibitin as a vitamin D target gene. Confocal microscopic analysis showed that Prohibitin was localized in the nuclei of MCF-7 cells and a portion of Prohibitin was colocalized with VDR, but direct physical interaction between VDR and Prohibitin in cell lysates was not detectable. In MCF-7 cells expressing tetracycline-inducible Prohibitin (Tet-On model), the overexpression of Prohibitin inhibited cell proliferation and enhanced vitamin D-induced antiproliferative activity. Knockdown of Prohibitin was accompanied by increased number of cells incorporating bromodeoxyuridine in the whole population and increased cell distribution in the S phase of cell cycle. In addition, Prohibitin level had no significant effect on the vitamin D-induced transactivation of CYP24, a VDR target gene. This is the first report to suggest that Prohibitin serves as a novel vitamin D target gene, which is involved in the antiproliferative action of vitamin D without affecting CYP24 transactivation in breast cancer cells.
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Prohibitin Facilitates Cellular Senescence by Recruiting Specific Corepressors To Inhibit E2F Target Genes
Molecular and cellular biology, 2006Co-Authors: Shipra Rastogi, Bharat H. Joshi, Piyali Dasgupta, Mark R. Morris, Kenneth L. Wright, Srikumar ChellappanAbstract:Prohibitin is a growth regulatory gene that has pleiotropic functions in the nucleus, mitochondria, and cytoplasmic compartments. Earlier studies had proposed a role for Prohibitin in modulating cellular senescence, but the underlying mechanisms remain unknown. Here we show that senescence induced by DNA-damaging agents causes the localization of Prohibitin to specific heterochromatic foci. Prohibitin could bind to heterochromatin protein 1 (HP1) family proteins and colocalized with HP1gamma in senescence-associated heterochromatic foci. Further, HP1gamma could synergize with Prohibitin to repress E2F1-mediated transcriptional activity. The depletion of Prohibitin by small interfering RNA or antisense techniques led to a reduction in the senescent phenotype, correlating with a reduced expression of senescence-associated beta-galactosidase and fewer numbers of senescence-associated heterochromatic foci. Chromatin immunoprecipitation assays showed that Prohibitin is needed for the recruitment of HP1gamma to E2F1-regulated proliferative promoters, leading to their repression. The ablation of Prohibitin prevented the recruitment of HPIgamma, but not Suv39H, to the promoters upon senescence. Prohibitin-mediated recruitment of HP1gamma occurred in only senescent cells, not in quiescent cells; thus, there is a dichotomy in the recruitment of different corepressors by Prohibitin, depending on the type of growth arrest. These studies show that Prohibitin plays a vital role in inducing cellular senescence.
Kelwyn Thomas - One of the best experts on this subject based on the ideXlab platform.
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Prohibitins Role in Cellular Survival Through Ras‐Raf‐MEK‐ERK Pathway
Journal of cellular physiology, 2014Co-Authors: Indrajit Chowdhury, Winston E Thompson, Kelwyn ThomasAbstract:Prohibitins are members of a highly conserved protein family containing the stomatin/Prohibitin/flotillin/HflK/C (SPFH) domain (also known as the Prohibitin [PHB] domain) found in unicellular eukaryotes, fungi, plants, animals, and humans. Two highly homologous members of Prohibitins expressed in eukaryotes are Prohibitin (PHB; B-cell receptor associated protein-32, BAP-32) and Prohibitin 2/repressor of estrogen receptor activity (PHB2, REA, BAP-37). Both PHB and REA/PHB2 are ubiquitously expressed and are present in multiple cellular compartments including the mitochondria, nucleus, and the plasma membrane. Multiple functions have been attributed to the mitochondrial and nuclear PHB and PHB2/REA including cellular differentiation, anti-proliferation, and morphogenesis. One of the major functions of the Prohibitins are in maintaining the functional integrity of the mitochondria and protecting cells from various stresses. In the present review, we focus on the recent research developments indicating that PHB and PHB2/REA are involved in maintaining cellular survival through the Ras-Raf-MEK-Erk pathway. Understanding the molecular mechanisms by which the intracellular signaling pathways utilize Prohibitins in governing cellular survival is likely to result in development of therapeutic strategies to overcome various human pathological disorders such as diabetes, obesity, neurological diseases, inflammatory bowel disease, and cancer.
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The emerging roles of Prohibitins in folliculogenesis.
Frontiers in bioscience (Elite edition), 2012Co-Authors: Indrajit Chowdhury, Kelwyn Thomas, Minerva T. Garcia-barrio, Djana Harp, Roland Matthews, Winston E ThompsonAbstract:Prohibitins are members of a highly conserved eukaryotic protein family containing the stomatin/Prohibitin/flotillin/HflK/C (SPFH) domain (also known as the Prohibitin (PHB) domain) found in divergent species from prokaryotes to eukaryotes. Prohibitins are found in unicellular eukaryotes, fungi, plants, animals and humans. Prohibitins are ubiquitously expressed and present in multiple cellular compartments including the mitochondria, nucleus, and the plasma membrane, and shuttles between the mitochondria, cytosol and nucleus. Multiple functions have been attributed to the mitochondrial and nuclear Prohibitins, including cellular differentiation, anti-proliferation, and morphogenesis. In the present review, we focus on the recent developments in Prohibitins research related to folliculogenesis. Based on current research findings, the data suggest that these molecules play important roles in modulating specific responses of granulose cells to follicle stimulating hormone (FSH) by acting at multiple levels of the FSH signal transduction pathway. Understanding the molecular mechanisms by which the intracellular signaling pathways utilize Prohibitins in governing folliculogenesis is likely to result in development of strategies to overcome fertility disorders and suppress ovarian cancer growth.
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Characterization of Prohibitin in a newly established rat ovarian granulosa cell line.
Endocrinology, 2001Co-Authors: Winston E Thompson, Alicia Branch, Joseph A. Whittaker, Deborah Lyn, Mosher Zilberstein, Kelly E. Mayo, Kelwyn ThomasAbstract:Prohibitin is an evolutionary conserved protein that is associated with cellular differentiation, atresia, and luteolysis in the rat ovary. However, the specific cellular location and function of Prohibitin in ovarian cells has not been clearly elucidated. To characterize the expression of Prohibitin during cell proliferation, differentiation, and cell death, we have successfully established a temperature-sensitive granulosa cell line, designated RGA-1. At a permissive temperature of 33 C, RGA-1 cells proliferate, but revert to a differentiated phenotype at a nonpermissive temperature of 39 C. Significant inductions of Prohibitin mRNA and protein expression were observed in the differentiated phenotype when compared with proliferating cells. Differentiated RGA-1 cells were found to express inhibin alpha- and beta-transcripts, as well as steroidogenic acute regulatory protein and peripheral-type benzodiazepine receptor proteins in a manner reminiscent of steroidogenic functional responses observed in primary differentiated granulosa cells. Prohibitin expression correlated well with the expression of these steroidogenic proteins. At 39 C, RGA-1 cells also displayed increases in p53 protein levels, indicative of growth arrest in the nonproliferating cells. Confocal and electron microscopic examinations revealed increased Prohibitin localization to the mitochondria at 39 C, along with changes in mitochondrial size and shape. These changes were accompanied by marked reductions in cytochrome c oxidase subunit II levels and in unit mitochondrial transmembrane potential. In addition, cell fractionation studies demonstrated that the Prohibitin protein was mainly localized to the mitochondrial membrane. Collectively, these findings suggest a role for Prohibitin in mitochondrial structure and function during growth and differentiation in ovarian granulosa cells. Prohibitin expression may also be indicative of mitochondrial destabilization during apoptosis-related events.
Gregor P. C. Drummen - One of the best experts on this subject based on the ideXlab platform.
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Prohibitin is associated with antioxidative protection in hypoxia/reoxygenation-induced renal tubular epithelial cell injury
Scientific reports, 2013Co-Authors: Tian-biao Zhou, Yuan-han Qin, Feng-ying Lei, Wei-fang Huang, Gregor P. C. DrummenAbstract:Prohibitin is an evolutionary conserved and pleiotropic protein that has been implicated in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. We recently demonstrated that Prohibitin downregulation results in increased renal interstitial fibrosis. Here we investigated the role of oxidative stress and Prohibitin expression in a hypoxia/reoxygenation injury system in renal tubular epithelial cells with lentivirus-based delivery vectors to knockdown or overexpress Prohibitin. Our results show that increased Prohibitin expression was negatively correlated with reactive oxygen species, malon dialdehyde, transforming-growth-factor-β1, collagen-IV, fibronectin, and apoptosis (r = −0.895, −0.764, −0.798, −0.826, −0.817, −0.735; each P < 0.01), but positively correlated with superoxide dismutase, glutathione and mitochondrial membrane potential (r = 0.807, 0.815, 0.739; each P < 0.01). We postulate that Prohibitin acts as a positive regulator of mechanisms that counteract oxidative stress and extracellular matrix accumulation and therefore has an antioxidative effect.
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Prohibitin attenuates oxidative stress and extracellular matrix accumulation in renal interstitial fibrosis disease.
PloS one, 2013Co-Authors: Tian-biao Zhou, Yuan-han Qin, Feng-ying Lei, Wei-fang Huang, Gregor P. C. DrummenAbstract:Prohibitin is an evolutionary conserved and pleiotropic protein that has been implicated in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. Both Prohibitin over- and under-expression have been implicated in various diseases and cell types. We recently demonstrated that Prohibitin down-regulation results in increased renal interstitial fibrosis (RIF). Here we investigated the role of oxidative stress and Prohibitin expression in RIF in unilateral ureteral obstructed rats. Lentivirus-based delivery vectors were used to knockdown or over-express Prohibitin. Our results show that increased Prohibitin expression was negatively correlated with the RIF index, reactive oxygen species, malon dialdehyde, transforming growth factor β1, collagen IV, fibronectin, and cell apoptosis index. In conclusion, we postulate that Prohibitin acts as a positive regulator of mechanisms that counteract oxidative stress and extracellular matrix accumulation and therefore has an antioxidative effect.
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Prohibitin is associated with antioxidative protection in hypoxia/ reoxygenation-induced renal tubular
2013Co-Authors: Tian-biao Zhou, Yuan-han Qin, Feng-ying Lei, Wei-fang Huang, Gregor P. C. DrummenAbstract:Prohibitin is an evolutionary conserved and pleiotropic protein that has been implicated in various cellular functions, including proliferation, tumour suppression, apoptosis, transcription, and mitochondrial protein folding. We recently demonstrated that Prohibitin downregulation results in increased renal interstitial fibrosis. Here we investigated the role of oxidative stress and Prohibitin expression in a hypoxia/ reoxygenation injury system in renal tubular epithelial cells with lentivirus-based delivery vectors to knockdown or overexpress Prohibitin. Our results show that increased Prohibitin expression was negatively correlated with reactive oxygen species, malon dialdehyde, transforming-growth-factor-b1, collagen-IV, fibronectin, and apoptosis (r 52 0.895, 20.764, 20.798, 20.826, 20.817, 20.735; each P , 0.01), but positively correlated with superoxide dismutase, glutathione and mitochondrial membrane potential (r 5 0.807, 0.815, 0.739; each P , 0.01). We postulate that Prohibitin acts as a positive regulator of mechanisms that counteract oxidative stress and extracellular matrix accumulation and therefore has an antioxidative effect.
Sheng Wang - One of the best experts on this subject based on the ideXlab platform.
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Roles of Prohibitin in growth control and tumor suppression in human cancers.
Translational oncogenomics, 2008Co-Authors: Sheng Wang, Douglas V. FallerAbstract:Tumor formation results from alterations in the normal control of cell proliferation. In the past decade, much attention in cancer research has been focused on the function of proto-oncogenes and tumor suppressors. Prohibitin is a potential tumor suppressor which was originally identified because of its anti-proliferative activities. Subsequent investigations led to the discovery of Prohibitin mutations in sporadic breast cancers. Recent studies established that Prohibitin directly regulates E2F-mediated transcription and growth suppression Prohibitin further attracted the attention of the translational cancer research community when it was recently connected to the regulation of estrogen receptor and androgen receptor activity. Prohibitin was shown to be required for the growth suppression of breast cancer cells induced by estrogen antagonists, and for therapeutic responses to androgen antagonists in prostate cancer. Through the application of new molecular technologies, additional novel functions of Prohibitin have been revealed, demonstrating diverse and essential roles of this highly-conserved protein in regulating cell growth.
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Prohibitin is a novel target gene of vitamin D involved in its antiproliferative action in breast cancer cells.
Cancer research, 2006Co-Authors: Xinjian Peng, Sheng Wang, Srikumar Chellappan, Rajeshwari R. Mehta, Rajendra G. MehtaAbstract:Previously, we showed that N-methyl-N-nitrosourea-transformed MCF12F breast epithelial cells exhibited differential expression of several genes, including up-regulation of Prohibitin and elevated sensitivity to a relatively noncalcemic vitamin D analogue, 1alpha-hydroxyvitamin D5 [1alpha(OH)D5]. In this report, we evaluated the functional significance of Prohibitin in relation to the cellular response to vitamin D. The in silico screening for putative transcription factor binding sites identified two vitamin D receptor (VDR)/retinoid X receptor binding sites in the 1-kb promoter region of Prohibitin. Prohibitin up-regulation by 1alpha(OH)D5 treatment at both transcriptional and translational levels was confirmed by real-time reverse transcription-PCR and Western blot analysis in breast cancer cells, identifying Prohibitin as a vitamin D target gene. Confocal microscopic analysis showed that Prohibitin was localized in the nuclei of MCF-7 cells and a portion of Prohibitin was colocalized with VDR, but direct physical interaction between VDR and Prohibitin in cell lysates was not detectable. In MCF-7 cells expressing tetracycline-inducible Prohibitin (Tet-On model), the overexpression of Prohibitin inhibited cell proliferation and enhanced vitamin D-induced antiproliferative activity. Knockdown of Prohibitin was accompanied by increased number of cells incorporating bromodeoxyuridine in the whole population and increased cell distribution in the S phase of cell cycle. In addition, Prohibitin level had no significant effect on the vitamin D-induced transactivation of CYP24, a VDR target gene. This is the first report to suggest that Prohibitin serves as a novel vitamin D target gene, which is involved in the antiproliferative action of vitamin D without affecting CYP24 transactivation in breast cancer cells.
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Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression
Oncogene, 2002Co-Authors: Sheng Wang, Gina Fusaro, Jaya Padmanabhan, Srikumar P ChellappanAbstract:The potential tumor suppressor protein Prohibitin can prevent cell proliferation and this required its binding to the Rb protein. Prohibitin could repress the transcriptional activity of E2F family members and this required a part of the marked box region of E2F. The sub-cellular localization of Prohibitin has been variously attributed to the mitochondria as well as the inner cell membrane. Here we show that a subset of Prohibitin molecules are present in the nucleus where it co-localizes with the Rb protein. Deletion of a putative amino-terminal membrane-docking domain of Prohibitin had no effect on its ability to suppress cell proliferation or inhibit E2F activity. Our experiments show that a 53 amino-acid stretch of E2F1 is sufficient for being targeted by Prohibitin; fusion of this region to GAL4–VP16 construct could make it susceptible to Prohibitin-mediated, but not Rb-mediated repression. Prohibitin, like Rb, could repress transcription from SV40 and major late promoters when recruited directly to DNA. Prohibitin mediated transcriptional repression required histone-deacetylase activity, but unlike Rb, additional co-repressors like N-CoR are also involved. Repression by Prohibitin correlates with histone deacetylation on promoters and this was reversed by IgM stimulation of cells; IgM did not affect Rb-mediated repression or deacetylation of the promoters. Prohibitin thus appears to repress E2F-mediated transcription utilizing different molecular mediators and facilitate channeling of specific signaling pathways to the cell cycle machinery.
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Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth.
The EMBO journal, 2002Co-Authors: Sheng Wang, Baohua Zhang, Douglas V. FallerAbstract:E2F transcription factors play a major role in controlling mammalian cell cycle progression. We recently reported that a potential tumor suppressor, Prohibitin, which interacts with retinoblastoma protein (Rb), regulates E2F function and this activity correlates with its growth-suppressive activity. We show here that Prohibitin recruits Brg-1/Brm to E2F-responsive promoters, and that this recruitment is required for the repression of E2F-mediated transcription by Prohibitin. Expression of a dominant-negative Brg-1 or Brm releases Prohibitin-mediated repression of E2F and relieves Prohibitin-mediated growth suppression. Although Prohibitin associates with, and recruits, Brg-1 and Brm independently of Rb, Prohibitin/Brg-1/Brm-mediated transcriptional repression requires Rb. A viral oncoprotein, SV40 large T antigen, can reverse Prohibitin-mediated suppression of E2F-mediated gene transcription, and targets Prohibitin through interruption of the association between Prohibitin and Brg-1/Brm without affecting the Prohibitin–E2F interaction.
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Rb and Prohibitin Target Distinct Regions of E2F1 for Repression and Respond to Different Upstream Signals
Molecular and cellular biology, 1999Co-Authors: Sheng Wang, Gina Fusaro, Niharika Nath, Srikumar ChellappanAbstract:E2F transcription factor is subject to stringent regulation by a variety of molecules. We recently observed that Prohibitin, a potential tumor suppressor protein, binds to the retinoblastoma (Rb) protein and represses E2F transcriptional activity. Here we demonstrate that Prohibitin requires the marked box region of E2F for repression; further, Prohibitin can effectively inhibit colony formation induced by overexpression of E2F1 in T47D cells. Prohibitin was also found to interact with the signaling kinase c-Raf-1, and Raf-1 could effectively reverse Prohibitin-mediated repression of E2F activity. Agents such as E1A, p38 kinase, and cyclins D and E had no effect on Prohibitin-mediated repression of E2F1, but all of these molecules could reverse Rb function. Similarly, stimulation of the immunoglobulin M signaling pathway in Ramos cells could inactivate Prohibitin, but this had no effect on Rb function. Serum stimulation of quiescent Ramos cells inactivated Rb and Prohibitin with different kinetics; further, while the serum-dependent inactivation of Rb was dependent on cyclin-dependent kinase activity, the inactivation of Prohibitin was not. We believe that Prohibitin is a novel regulator of E2F function which channels specific signaling cascades to the cell cycle regulatory machinery.
Thomas Rudel - One of the best experts on this subject based on the ideXlab platform.
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Prohibitins are required for cancer cell proliferation and adhesion.
PloS one, 2010Co-Authors: Claudia Sievers, Gwendolyn Billig, Kathleen Gottschalk, Thomas RudelAbstract:Prohibitin 1 (PHB1) is a highly conserved protein that together with its homologue Prohibitin 2 (PHB2) mainly localizes to the inner mitochondrial membrane. Although it was originally identified by its ability to inhibit G1/S progression in human fibroblasts, its role as tumor suppressor is debated. To determine the function of Prohibitins in maintaining cell homeostasis, we generated cancer cell lines expressing Prohibitin-directed shRNAs. We show that Prohibitin proteins are necessary for the proliferation of cancer cells. Down-regulation of Prohibitin expression drastically reduced the rate of cell division. Furthermore, mitochondrial morphology was not affected, but loss of Prohibitins did lead to the degradation of the fusion protein OPA1 and, in certain cancer cell lines, to a reduced capability to exhibit anchorage-independent growth. These cancer cells also exhibited reduced adhesion to the extracellular matrix. Taken together, these observations suggest Prohibitins play a crucial role in adhesion processes in the cell and thereby sustaining cancer cell propagation and survival.
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Prohibitin is required for Ras-induced Raf-MEK-ERK activation and epithelial cell migration
Nature cell biology, 2005Co-Authors: Krishnaraj Rajalingam, Claudia Sievers, Christian Wunder, Volker Brinkmann, Yuri Churin, Mirko Hekman, Ulf R. Rapp, Thomas RudelAbstract:Ras proteins control the signalling pathways that are responsible for normal growth and malignant transformation. Raf protein kinases are direct Ras effector proteins that initiate the mitogen-activated protein kinase (MAPK) cascade, which mediates diverse biological functions such as cell growth, survival and differentiation. Here we show that Prohibitin, a ubiquitously expressed and evolutionarily conserved protein is indispensable for the activation of the Raf-MEK-ERK pathway by Ras. The membrane targeting and activation of C-Raf by Ras needs Prohibitin in vivo. In addition, direct interaction with Prohibitin is required for C-Raf activation. C-Raf kinase fails to interact with the active Ras induced by epidermal growth factor in the absence of Prohibitin. Moreover, in Prohibitin-deficient cells the adhesion complex proteins cadherin and beta-catenin relocalize to the plasma membrane and thereby stabilize adherens junctions. Our data show an unexpected role of Prohibitin in the activation of the Ras-Raf signalling pathway and in modulating epithelial cell adhesion and migration.
