pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes.

The activity of the E2F transcription factor is controlled by physical association with the retinoblastoma protein (pRB) and two related proteins, p107 and p130. The pRB family members are thought to control different aspects of E2F activity, but it has been unclear what the respective functions of these proteins might be. To dissect the specific functions of pRB, p107, and p130 we have investigated how the expression of E2F-regulated genes is changed in cultures of primary cells lacking each of these family members. Whereas no changes were found in the expression of E2F-target genes in cells lacking either p107 or p130, deregulated expression of E2F targets was seen in cells lacking pRB and in cells lacking both p107 and p130. Surprisingly, the genes that were disregulated in these two settings were completely different. These findings show that pRB and p107/p130 indeed provide different functions in E2F regulation and identify target genes that are dependent on pRB family proteins for their normal expression.

[1]  P. Farnham,et al.  Position-dependent transcriptional regulation of the murine dihydrofolate reductase promoter by the E2F transactivation domain , 1997, Molecular and cellular biology.

[2]  C. Sherr Cancer Cell Cycles , 1996, Science.

[3]  D. Livingston,et al.  The retinoblastoma gene product protects E2F-1 from degradation by the ubiquitin-proteasome pathway. , 1996, Genes & development.

[4]  A. Shvarts,et al.  Degradation of E2F by the ubiquitin-proteasome pathway: regulation by retinoblastoma family proteins and adenovirus transforming proteins. , 1996, Genes & development.

[5]  R. Weinberg,et al.  Increased histone H1 phosphorylation and relaxed chromatin structure in Rb-deficient fibroblasts. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[6]  A. Schulze,et al.  Copyright � 1996, American Society for Microbiology Anchorage-Dependent Transcription of the Cyclin A Gene , 1996 .

[7]  E. Harlow A research shortcut from a common cold virus to human cancer , 1996, Cancer.

[8]  T. Jacks,et al.  Targeted disruption of p107: functional overlap between p107 and Rb. , 1996, Genes & development.

[9]  A. Hatzigeorgiou,et al.  Cell cycle regulation of the murine cyclin E gene depends on an E2F binding site in the promoter , 1996, Molecular and cellular biology.

[10]  R. Weinberg,et al.  Shared role of the pRB-related p130 and p107 proteins in limb development. , 1996, Genes & development.

[11]  J. Blanchard,et al.  Cyclin A expression is under negative transcriptional control during the cell cycle , 1996, Molecular and cellular biology.

[12]  B. Dynlacht,et al.  Transcriptional control of the cell cycle. , 1996, Current opinion in cell biology.

[13]  R. Weinberg,et al.  Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb-deficient fibroblasts , 1996, Molecular and cellular biology.

[14]  K. Moberg,et al.  E2F-4 switches from p130 to p107 and pRB in response to cell cycle reentry , 1996, Molecular and cellular biology.

[15]  E. Wintersberger,et al.  Interaction of Sp1 with the growth- and cell cycle-regulated transcription factor E2F , 1996, Molecular and cellular biology.

[16]  R. Weinberg,et al.  Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. , 1996, Oncogene.

[17]  J. Bartek,et al.  Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression , 1996, Molecular and cellular biology.

[18]  P. Farnham,et al.  Introduction to the E2F family: protein structure and gene regulation. , 1996, Current topics in microbiology and immunology.

[19]  W. Kaelin,et al.  The cellular effects of E2F overexpression. , 1996, Current topics in microbiology and immunology.

[20]  D. Cobrinik Regulatory interactions among E2Fs and cell cycle control proteins. , 1996, Current topics in microbiology and immunology.

[21]  J. Nevins,et al.  Regulation of the cyclin E gene by transcription factor E2F1. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[22]  G. Pfeifer,et al.  In vivo structure of the human cdc2 promoter: release of a p130-E2F-4 complex from sequences immediately upstream of the transcription initiation site coincides with induction of cdc2 expression , 1995, Molecular and cellular biology.

[23]  A. Schulze,et al.  Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[24]  P. Branton,et al.  Characterization of transcription factor E2F complexes during muscle and neuronal differentiation. , 1995, Oncogene.

[25]  F. C. Lucibello,et al.  Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression. , 1995, The EMBO journal.

[26]  M. Soonpaa,et al.  Developmental expression of p107 mRNA and evidence for alternative splicing of the p107 (RBL1) gene product. , 1995, Genomics.

[27]  J. Nevins,et al.  Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and G1/S-regulatory genes , 1995, Molecular and cellular biology.

[28]  Lingyun Zhu,et al.  Differential roles of two tandem E2F sites in repression of the human p107 promoter by retinoblastoma and p107 proteins , 1995, Molecular and cellular biology.

[29]  S. Weintraub,et al.  Mechanism of active transcriptional repression by the retinoblastoma protein , 1995, Nature.

[30]  G. Wahl,et al.  Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[31]  L. J. Veer,et al.  E2F-5, a new E2F family member that interacts with p130 in vivo , 1995, Molecular and cellular biology.

[32]  R. Weinberg,et al.  The retinoblastoma protein and cell cycle control , 1995, Cell.

[33]  J. Bartek,et al.  Cyclin D1 is dispensable for G1 control in retinoblastoma gene-deficient cells independently of cdk4 activity , 1995, Molecular and cellular biology.

[34]  W. Sellers,et al.  Transcription of the E2F-1 gene is rendered cell cycle dependent by E2F DNA-binding sites within its promoter , 1994, Molecular and cellular biology.

[35]  D. Riley,et al.  The retinoblastoma protein as a fundamental mediator of growth and differentiation signals. , 1995, Critical reviews in eukaryotic gene expression.

[36]  P. J. Welch,et al.  Disruption of retinoblastoma protein function by coexpression of its C pocket fragment. , 1995, Genes & development.

[37]  Y. Liu,et al.  Regulation of cyclin D1, DNA topoisomerase I, and proliferating cell nuclear antigen promoters during the cell cycle. , 1995, Gene expression.

[38]  J. Lawrence,et al.  E2F-4, a new member of the E2F transcription factor family, interacts with p107. , 1994, Genes & development.

[39]  L. Zhu,et al.  E2F-4, a new member of the E2F gene family, has oncogenic activity and associates with p107 in vivo. , 1994, Genes & development.

[40]  A. Bradley,et al.  Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation. , 1994, Genes & development.

[41]  J. Swantek,et al.  An E2F binding sequence negatively regulates the response of the insulin-like growth factor 1 (IGF-I) promoter to simian virus 40T antigen and to serum. , 1994, Oncogene.

[42]  P. Farnham,et al.  Multiple DNA elements are required for the growth regulation of the mouse E2F1 promoter. , 1994, Genes & development.

[43]  J. Nevins,et al.  Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression. , 1994, Genes & development.

[44]  W. Gu,et al.  Reversal of terminal differentiation mediated by p107 in Rb-/- muscle cells. , 1994, Science.

[45]  T. Dryja,et al.  A silencer element in the retinoblastoma tumor-suppressor gene. , 1994, Oncogene.

[46]  K. Alitalo,et al.  Repression of cyclin D1: a novel function of MYC. , 1994, Molecular and cellular biology.

[47]  B. Gallie,et al.  Characterization of the human RB1 promoter and of elements involved in transcriptional regulation. , 1994, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[48]  M. Gossen,et al.  Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. , 1994, Molecular and cellular biology.

[49]  F. C. Lucibello,et al.  Inducible acceleration of G1 progression through tetracycline-regulated expression of human cyclin E. , 1994, Oncogene.

[50]  W. Lee,et al.  The transcription factor E2F-1 mediates the autoregulation of RB gene expression , 1994, Molecular and cellular biology.

[51]  M. Ewen,et al.  Analysis of p107-associated proteins: p107 associates with a form of E2F that differs from pRB-associated E2F-1 , 1993, Journal of virology.

[52]  R. Weinberg,et al.  Cell cycle-specific association of E2F with the p130 E1A-binding protein. , 1993, Genes & development.

[53]  M. Vidal,et al.  The retinoblastoma protein binds to a family of E2F transcription factors , 1993, Molecular and cellular biology.

[54]  J. Nevins,et al.  A genetic analysis of the E2F1 gene distinguishes regulation by Rb, p107, and adenovirus E4. , 1993, Molecular and cellular biology.

[55]  J. Nevins,et al.  Expression of transcription factor E2F1 induces quiescent cells to enter S phase , 1993, Nature.

[56]  D. Livingston,et al.  Cell cycle analysis of E2F in primary human T cells reveals novel E2F complexes and biochemically distinct forms of free E2F , 1993, Molecular and cellular biology.

[57]  E. Lam,et al.  An E2F‐binding site mediates cell‐cycle regulated repression of mouse B‐myb transcription. , 1993, The EMBO journal.

[58]  M. Ewen,et al.  Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein. , 1993, Genes & development.

[59]  A. Pichler,et al.  A binding site for transcription factor E2F is a target for trans activation of murine thymidine kinase by polyomavirus large T antigen and plays an important role in growth regulation of the gene , 1993, Journal of virology.

[60]  James M. Roberts,et al.  Cyclin-dependent regulation of G1 in mammalian fibroblasts. , 1993, Science.

[61]  P. Farnham,et al.  A protein synthesis-dependent increase in E2F1 mRNA correlates with growth regulation of the dihydrofolate reductase promoter , 1993, Molecular and cellular biology.

[62]  J. Nevins,et al.  Interactions of the p107 and Rb proteins with E2F during the cell proliferation response. , 1993, The EMBO journal.

[63]  D. Templeton,et al.  Biological function of the retinoblastoma protein requires distinct domains for hyperphosphorylation and transcription factor binding , 1992, Molecular and cellular biology.

[64]  A. Berns,et al.  Requirement for a functional Rb-1 gene in murine development , 1992, Nature.

[65]  R. Weinberg,et al.  Effects of an Rb mutation in the mouse , 1992, Nature.

[66]  A. Bradley,et al.  Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis , 1992, Nature.

[67]  B. Gallie,et al.  Transcriptional repression of the E2-containing promoters EIIaE, c-myc, and RB1 by the product of the RB1 gene. , 1992, Molecular and cellular biology.

[68]  S. Weintraub,et al.  Retinoblastoma protein switches the E2F site from positive to negative element , 1992, Nature.

[69]  S. Dalton,et al.  Cell cycle regulation of the human cdc2 gene. , 1992, The EMBO journal.

[70]  L. Johnson G1 events and the regulation of genes for S-phase enzymes. , 1992, Current opinion in cell biology.

[71]  P. Farnham,et al.  The HIP1 binding site is required for growth regulation of the dihydrofolate reductase gene promoter , 1992, Molecular and cellular biology.

[72]  M. Ewen,et al.  The transcription factor E2F interacts with the retinoblastoma product and a p107-cyclin A complex in a cell cycle-regulated manner , 1992, Cell.

[73]  J. Nevins,et al.  A cyclin A-protein kinase complex possesses sequence-specific DNA binding activity: p33cdk2 is a component of the E2F-cyclin A complex , 1992, Cell.

[74]  L. Tsai,et al.  Independent binding of the retinoblastoma protein and p107 to the transcription factor E2F , 1992, Nature.

[75]  J. Laborda,et al.  36B4 cDNA used as an estradiol-independent mRNA control is the cDNA for human acidic ribosomal phosphoprotein PO. , 1991, Nucleic acids research.

[76]  H. Nasheuer,et al.  Human DNA polymerase alpha gene: sequences controlling expression in cycling and serum-stimulated cells , 1991, Molecular and cellular biology.

[77]  M Lipp,et al.  E1A-dependent trans-activation of the human MYC promoter is mediated by the E2F factor. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[78]  M Lipp,et al.  Nuclear factor E2F mediates basic transcription and trans-activation by E1a of the human MYC promoter. , 1989, Genes & development.

[79]  J. Nevins,et al.  Promoter interaction of the E1A‐inducible factor E2F and its potential role in the formation of a multi‐component complex. , 1987, The EMBO journal.

[80]  B. Henglein,et al.  Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E 2 F site , 2022 .