Work

p400 Is Required for E1A to Promote Apoptosis

Year: 2005

Type: article

Abstract: The adenovirus E1A oncoprotein promotes proliferation and transformation by binding cellular proteins, including members of the retinoblastoma protein family, the p300/CREB-binding protein transcriptional coactivators, and the p400-TRRAP chromatin-remodeling complex. E1A also promotes apoptosis, in part, by engaging the ARF-p53 tumor suppressor pathway. We show that E1A induces ARF and p53 and promotes apoptosis in normal fibroblasts by physically associating with the retinoblastoma protein and a p400-TRRAP complex and that its interaction with p300 is largely dispensable for these effects. We further show that E1A increases p400 expression and, conversely, that suppression of p400 using stable RNA interference reduces the levels of ARF, p53, and apoptosis in E1A-expressing cells. Therefore, whereas E1A inactivates the retinoblastoma protein, it requires p400 to efficiently promote cell death. These results identify p400 as a regulator of the ARF-p53 pathway and a component of the cellular machinery that couples proliferation to cell death. The adenovirus E1A oncoprotein promotes proliferation and transformation by binding cellular proteins, including members of the retinoblastoma protein family, the p300/CREB-binding protein transcriptional coactivators, and the p400-TRRAP chromatin-remodeling complex. E1A also promotes apoptosis, in part, by engaging the ARF-p53 tumor suppressor pathway. We show that E1A induces ARF and p53 and promotes apoptosis in normal fibroblasts by physically associating with the retinoblastoma protein and a p400-TRRAP complex and that its interaction with p300 is largely dispensable for these effects. We further show that E1A increases p400 expression and, conversely, that suppression of p400 using stable RNA interference reduces the levels of ARF, p53, and apoptosis in E1A-expressing cells. Therefore, whereas E1A inactivates the retinoblastoma protein, it requires p400 to efficiently promote cell death. These results identify p400 as a regulator of the ARF-p53 pathway and a component of the cellular machinery that couples proliferation to cell death. Normal cells possess innate tumor suppressor mechanisms that couple proliferation to apoptosis, thereby limiting the transforming potential of oncogenic mutations (reviewed in Ref. 1Lowe S.W. Cepero E. Evan G. Nature. 2004; 432: 307-315Crossref PubMed Scopus (1056) Google Scholar). For example, overexpression of the c-myc oncogene or loss of the retinoblastoma protein (Rb) 1The abbreviations used are: Rb, retinoblastoma protein; CBP, CREB-binding protein; cAMP-response element-binding protein; MEF, mouse embryo fibroblast; shRNA, short hairpin RNA. tumor suppressor deregulates cell cycle control but also can promote apoptosis. Consequently, cells with these lesions proliferate inappropriately but also become hypersensitive to apoptosis in response to survival factor depletion and DNA-damaging agents. Subsequent mutations that disable apoptosis allow proliferation to continue unabated, leading to oncogenic transformation or tumor progression. The ARF-p53 pathway is an important circuit in the signaling network that couples proliferation to cell death (2Sherr C.J. Nat. Rev. Mol. Cell. Biol. 2001; 2: 731-737Crossref PubMed Scopus (826) Google Scholar). ARF is the alternative reading frame product of the INK4a/ARF tumor suppressor locus, which also encodes the cyclin-dependent kinase inhibitor p16INK4a. Several oncogenes, including c-Myc and E1A, induce ARF message and protein, which in turn activates p53 by interfering with its negative regulator Mdm2 (2Sherr C.J. Nat. Rev. Mol. Cell. Biol. 2001; 2: 731-737Crossref PubMed Scopus (826) Google Scholar). p53, in turn, increases the transcription of genes that ultimately target different components of the apoptotic machinery (3Fridman J.S. Lowe S.W. Oncogene. 2003; 22: 9030-9040Crossref PubMed Scopus (1153) Google Scholar). Although oncogenes can also promote apoptosis through ARF- and p53-independent mechanisms, apoptosis induced by Myc or E1A is severely compromised in cells lacking ARF or p53 (4Zindy F. Eischen C.M. Randle D.H. Kamijo T. Cleveland J.L. Sherr C.J. Roussel M.F. Genes Dev. 1998; 12: 2424-2433Crossref PubMed Scopus (1060) Google Scholar, 5de Stanchina E. McCurrach M.E. Zindy F. Shieh S.Y. Ferbeyre G. Samuelson A.V. Prives C. Roussel M.F. Sherr C.J. Lowe S.W. Genes Dev. 1998; 12: 2434-2442Crossref PubMed Scopus (546) Google Scholar), and loss of ARF or p53 can cooperate with proapoptotic oncogenes to promote transformation in vitro and tumorigenesis in mice (reviewed in Refs. 1Lowe S.W. Cepero E. Evan G. Nature. 2004; 432: 307-315Crossref PubMed Scopus (1056) Google Scholar and 6Lowe S.W. Sherr C.J. Curr. Opin. Genet. Dev. 2003; 13: 77-83Crossref PubMed Scopus (616) Google Scholar). How ARF senses hyperproliferative signals is poorly understood, but it can involve transcriptional control of the ARF promoter by E2F proteins as well as control of higher order chromatin structure by chromatin remodeling complexes (7Jacobs J.J. Scheijen B. Voncken J.W. Kieboom K. Berns A. van Lohuizen M. Genes Dev. 1999; 13: 2678-2690Crossref PubMed Scopus (539) Google Scholar, 8Bates S. Phillips A.C. Clark P.A. Stott F. Peters G. Ludwig R.L. Vousden K.H. Nature. 1998; 395: 124-125Crossref PubMed Scopus (812) Google Scholar, 9Aslanian A. Iaquinta P.J. Verona R. Lees J.A. Genes Dev. 2004; 18: 1413-1422Crossref PubMed Scopus (152) Google Scholar). The adenovirus E1A oncoprotein promotes uncontrolled cell cycle progression and apoptosis and has been widely used as a tool to identify cellular activities that function in both processes. E1A stimulates proliferation by physically associating with proteins that act at critical control points in the normal cell cycle (10Ben-Israel H. Kleinberger T. Front. Biosci. 2002; 7: 1369-1395Crossref PubMed Scopus (91) Google Scholar). Perhaps the best understood of these involve the Rb family, which interacts with the E1A protein through an LXCXE motif located in a central domain known as conserved region 2. As a consequence of this interaction, E1A inactivates the Rb family proteins, thereby releasing E2Fs to constitutively activate S phase genes. Notably, Rb inactivation is not sufficient for E1A action, and, in fact, N-terminal regions of E1A also contribute to promoting S phase entry and oncogenic transformation. For example, the N terminus of E1A binds and interferes with the function of p300 and CBP, two highly related transcriptional co-activators that stimulate the expression of genes involved in growth inhibition and differentiation (11Eckner R. Ewen M.E. Newsome D. Gerdes M. DeCaprio J.A. Lawrence J.B. Livingston D.M. Genes Dev. 1994; 8: 869-884Crossref PubMed Scopus (925) Google Scholar, 12Arany Z. Newsome D. Oldread E. Livingston D.M. Eckner R. Nature. 1995; 374: 81-84Crossref PubMed Scopus (491) Google Scholar). Also, E1A uses overlapping sequences to target p400 and TRRAP, two unrelated proteins that interact with each other and other additional proteins involved in chromatin remodeling (13Fuchs M. Gerber J. Drapkin R. Sif S. Ikura T. Ogryzko V. Lane W.S. Nakatani Y. Livingston D.M. Cell. 2001; 106: 297-307Abstract Full Full PubMed Scopus Google Scholar). The of genes by these complexes is not well understood, but the important for transforming of both E1A and Myc (13Fuchs M. Gerber J. Drapkin R. Sif S. Ikura T. Ogryzko V. Lane W.S. Nakatani Y. Livingston D.M. Cell. 2001; 106: 297-307Abstract Full Full PubMed Scopus Google Scholar, Cell. 1998; Full Full PubMed Scopus Google Scholar, S. K. B. H. Oncogene. 2001; PubMed Scopus Google Scholar, M. S. C. R. Cell. 2002; 2: Full Full PubMed Scopus Google Scholar). The cellular proteins by E1A to promote apoptosis apoptosis with the of E1A to J.S. K. Oncogene. 1994; Google Scholar, M. S. Oncogene. 1995; Google Scholar, E. J. PubMed Google Scholar, A.V. Lowe S.W. S. A. PubMed Scopus Google Scholar, M. S. R. G. K. J.S. J. M. J. Biol. 2004; Full Full PubMed Scopus Google Scholar). with the potential of this interaction, p300 can control p53 For example, complexes can interact with p53, and contribute to its that E1A binding to p300 to p53 by p53 M. M. C. S. Livingston D.M. Mol. Cell. 1998; 2: Full Full PubMed Scopus Google and E1A of p53 by p300 and Mdm2 M.E. C. H. Nakatani Y. 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PubMed Scopus Google Scholar). has the of of E1A thereby E1A to in normal cells the of adenovirus this that E1A uses at two that act in to induce ARF and p53 and promote apoptosis Stanchina E. McCurrach M.E. Zindy F. Shieh S.Y. Ferbeyre G. Samuelson A.V. Prives C. Roussel M.F. Sherr C.J. Lowe S.W. Genes Dev. 1998; 12: 2434-2442Crossref PubMed Scopus (546) Google Scholar, A.V. Lowe S.W. S. A. PubMed Scopus Google Scholar). domain conserved region which promotes apoptosis by binding and whereas E1A Rb family the apoptotic of E1A to Rb is in cells lacking region requires an N-terminal E1A domain that E1A sequences to the E1A used in and in not to other We a which RNA to identify and N-terminal of E1A involved it apoptosis. results in normal the interaction is largely dispensable for E1A to induce ARF, p53, and apoptosis. E1A a which is for its proapoptotic E1A and both the and M.E. C.M. Lowe S.W. S. A. PubMed Scopus Google Scholar). The has a at that a a a short hairpin with a a M. S. E. M. Lowe S.W. Cell. 2003; Full Full PubMed Scopus Google the in as As p400 short hairpin with promoter M. Lowe S.W. Livingston D.M. Genes Dev. PubMed Scopus Google an of which the As a control the promoter the in the the the reading frame or hairpin and fibroblasts and cells mouse embryo fibroblasts and used and cells at in using with and as M. McCurrach M.E. D. Lowe S.W. Cell. Full Full PubMed Scopus Google Scholar). an or with or and the using or by by with to and For cells at with and For each of in of with of a control to which and E1A and cells for or in inhibitor with for at for at at to levels using and with for at The used in as for E1A, E. C. J. PubMed Google for of E. J. PubMed Google for of (13Fuchs M. Gerber J. Drapkin R. Sif S. Ikura T. Ogryzko V. Lane W.S. Nakatani Y. Livingston D.M. Cell. 2001; 106: 297-307Abstract Full Full PubMed Scopus Google for of E. J. PubMed Google and for Rb, of and of C. D. E. Mol. Cell. Biol. PubMed Scopus Google Scholar). The of of of and with for an additional at with in and for and by to in and for at at in with and The used to of (11Eckner R. Ewen M.E. Newsome D. Gerdes M. DeCaprio J.A. Lawrence J.B. Livingston D.M. Genes Dev. 1994; 8: 869-884Crossref PubMed Scopus (925) Google E. J. PubMed Google and C. D. E. Mol. Cell. Biol. PubMed Scopus Google and For cell in by for by at for using a and by to or using of two for at at using a and or for at at using a and as The used to of or and using RNA by of RNA and to in at with in and The at in for at in for and at in for for ARF and S by in at for and in for at in normal for at and for at with a in The used and with and for at with and with for at in with and a with or and cells and for by cells for each death to apoptosis by chromatin with at apoptosis by cell death with of and of apoptosis of for and the of at by apoptosis the for E1A in the order to the apoptotic of E1A, an to the regions of E1A of binding cellular proteins with to the ARF-p53 pathway and to promote apoptosis. a of E1A that or in the N-terminal a that also a the S of E1A conserved regions and but not conserved region is sufficient to induce p53 and apoptosis S.W. Genes Dev. 7: PubMed Scopus Google Scholar), of the N-terminal in a S E1A a and normal fibroblasts or The in to and to for or E1A this a of cell or E1A and in Normal the regions of E1A for with transformation as CBP, and Rb been has these in normal cells. Therefore, to cell the of E1A to interact with CBP, and Rb in For and Rb, the results in normal fibroblasts largely to has been in other cell with in for binding p300 the region in and Refs. Y. B. E. J. PubMed Google Scholar and J.S. J. 1994; Google For example, the and to interact with p300 and but Rb the E1A interacts with p300 and but not Rb, whereas the E1A interacts with CBP, and Rb The N-terminal region of E1A is also for binding to p400-TRRAP chromatin-remodeling this interaction has not been Therefore, the of E1A to interact with p400 in or cells by in and in also Ref. M. Gerber J. Drapkin R. Sif S. Ikura T. Ogryzko V. Lane W.S. Nakatani Y. Livingston D.M. Cell. 2001; 106: 297-307Abstract Full Full PubMed Scopus Google E1A requires to interact with a region that is for p300 or Rb interaction The which has been (13Fuchs M. Gerber J. Drapkin R. Sif S. Ikura T. Ogryzko V. Lane W.S. Nakatani Y. Livingston D.M. Cell. 2001; 106: 297-307Abstract Full Full PubMed Scopus Google Scholar), is in that it binds p400-TRRAP its to interact with p300 and Rb and and and this a of the regions of E1A to interact with CBP, Rb, and p400 in normal cells that and or and p400-TRRAP for E1A to the regions of E1A to promote apoptosis. E1A can promote apoptosis in the of adenovirus E. R. A. J. PubMed Google Scholar, E. M. W.S. Mol. Cell. Biol. 12: PubMed Google Scholar, M. D. S. E. S. A. PubMed Scopus Google Scholar), cells can E1A but become highly to apoptosis with DNA-damaging or growth factor depletion S.W. T. Cell. Full PubMed Scopus Google Scholar, S.W. T. S. A. 1994; PubMed Scopus Google Scholar). Therefore, and cell an E1A, or E1A with a used known to and for cell by in in and that E1A-expressing cells apoptosis the used in this and using apoptotic chromatin and A.V. Lowe S.W. S. A. PubMed Scopus Google Scholar, M.E. C.M. Lowe S.W. S. A. PubMed Scopus Google Scholar, S.W. T. S. A. 1994; PubMed Scopus Google Scholar, S.W. S.W. T. Nature. PubMed Scopus Google Scholar, M. R. A. D. A. McCurrach M. G. T. Lowe S.W. Genes Dev. 1998; 12: PubMed Scopus Google Scholar). We also that death in these is by loss of p53 S.W. T. Cell. Full PubMed Scopus Google Scholar, S.W. T. S. A. 1994; PubMed Scopus Google or overexpression of the proteins or M.E. C.M. Lowe S.W. S. A. PubMed Scopus Google Scholar). this cell death to apoptotic by chromatin using M.E. C.M. Lowe S.W. S. A. PubMed Scopus Google and Rb binding by E1A is for in a the regions of E1A to promote apoptosis not with the to with the to p400 and Rb and As an example, the E1A its to interact with p400 but not apoptosis in response to and the E1A its to but not p400 and is at promoting apoptosis and p400 and complexes in cells lacking or E1A, and E1A to interact with p400 also to with (13Fuchs M. Gerber J. Drapkin R. Sif S. Ikura T. Ogryzko V. Lane W.S. Nakatani Y. Livingston D.M. Cell. 2001; 106: 297-307Abstract Full Full PubMed Scopus Google Scholar, S. K. B. H. Oncogene. 2001; PubMed Scopus Google Scholar). of to apoptosis, results in in the also show a apoptotic Therefore, a p400-TRRAP complex an important target of E1A in apoptosis. of ARF and p53 by E1A to also the of E1A for to activate the ARF-p53 pathway. p53 cells or each E1A to using a and with cells the regions of E1A for p53 with for apoptosis in both cell in For example, to but with p400-TRRAP and Rb and efficiently induces p53 and and whereas and binding but not p400-TRRAP or Rb, and at p53 and with and E1A also for ARF expression by and with to efficiently induce p53, cells or compromised in to induce ARF in with and and protein and and and not an in ARF We that the levels of E1A by the of induced ARF protein, which is with the known of this to p400 not also Ref. M. Gerber J. Drapkin R. Sif S. Ikura T. Ogryzko V. Lane W.S. Nakatani Y. Livingston D.M. Cell. 2001; 106: 297-307Abstract Full Full PubMed Scopus Google Scholar). Although this to ARF in and the E1A in its to induce ARF, and E1A ARF levels cellular to proapoptotic These results that E1A induces ARF and p53 by with Rb and a p400-TRRAP complex in turn, act to control ARF N-terminal E1A for that the domain of E1A can p300 of the N-terminal domain and can promote of cells in of cells by the binding protein Oncogene. PubMed Scopus Google Scholar). the E1A terminus for apoptosis in normal the E1A for its to induce apoptosis, ARF, and p53 in and cells. the domain and is to or binding protein but to and the Rb cells and E1A efficiently apoptosis in response to and not as cells a also lacking and to p300 not cells E1A to induce both ARF and p53 protein and not the N-terminal region of E1A is sufficient to promote apoptosis and activate p53, of its to physically with p300 and binding These results that E1A a of proteins, Rb and to apoptosis. p400 for with the interaction for apoptosis, a p400 of binding E1A, but not TRRAP, with apoptosis. of a conserved domain and is to that has been to both E1A and known as and can the transformation of E1A (13Fuchs M. Gerber J. Drapkin R. Sif S. Ikura T. Ogryzko V. Lane W.S. Nakatani Y. Livingston D.M. Cell. 2001; 106: 297-307Abstract Full Full PubMed Scopus Google Scholar). and D. M. cells E1A, and the for with a control cells apoptosis Although a this is with the that the interaction is important for apoptosis. E1A promote apoptosis by p400 conversely, by p400 E1A inactivates p400 the of E1A binds p400 to promote apoptosis. fact, an that the for conserved region in apoptosis involved its to Rb A.V. Lowe S.W. S. A. PubMed Scopus Google Scholar). E1A requires p400 to promote apoptosis, suppression of p400 cell death in cells these and to p400 to apoptosis, two short hairpin of p400 protein using RNA We each p400 and with a control E1A, or and the for ARF and p53 expression and to apoptosis. in the and in E1A induced p400 protein that is the p400 binding domain with that E1A not promote apoptosis by p400 normal both and efficiently p400 protein to and the cells a as in M. Lowe S.W. Livingston D.M. Genes Dev. PubMed Scopus Google Scholar). in cells E1A or to normal with and both and p400 levels to or normal E1A levels with cells E1A and p400 a in ARF and p53 protein, with cells a with these cells a in apoptosis with E1A-expressing cells a control results in and of expression of the p400 in a different a suppression of p400 and ARF or p53 levels or to apoptosis not As cells E1A a in ARF and p53 levels with these proteins further by expression of p400 to the p400 binding of this with and p400 the apoptotic of E1A Therefore, E1A not p400 to promote apoptosis requires p400 for cell death. this used the adenovirus E1A oncoprotein to the mechanisms normal cells couple proliferation and apoptosis in response to oncogenic We show in to binding the retinoblastoma E1A also with a complex to the ARF-p53 pathway and cells to apoptotic the E1A regions for binding p400 also for apoptosis, and of the interaction cell death. also show whereas E1A inactivates Rb, it requires p400 to promote apoptosis. E1A induces p400 protein, and suppression of p400 expression the of ARF, p53, and apoptosis in E1A-expressing cells. is that the of E1A to p400 is also important for its transforming potential (13Fuchs M. Gerber J. Drapkin R. Sif S. Ikura T. Ogryzko V. Lane W.S. Nakatani Y. Livingston D.M. Cell. 2001; 106: 297-307Abstract Full Full PubMed Scopus Google Scholar, S. K. B. H. Oncogene. 2001; PubMed Scopus Google Scholar, M. S. C. R. Cell. 2002; 2: Full Full PubMed Scopus Google Scholar). Therefore, results identify p400 as a component of the cellular machinery that couples proliferation to cell death. Although the of the E1A and Rb or p400 both E1A activities through to For example, E1A the interaction, E2F to constitutively activate target genes involved in cell cycle progression and apoptosis. the of E1A the normal of the p400 complex (13Fuchs M. Gerber J. Drapkin R. Sif S. Ikura T. Ogryzko V. Lane W.S. Nakatani Y. Livingston D.M. Cell. 2001; 106: 297-307Abstract Full Full PubMed Scopus Google Scholar). is a of complexes in chromatin remodeling including the and p400 complexes (13Fuchs M. Gerber J. Drapkin R. Sif S. Ikura T. Ogryzko V. Lane W.S. Nakatani Y. Livingston D.M. Cell. 2001; 106: 297-307Abstract Full Full PubMed Scopus Google Scholar, T. R.L. T. J. Nakatani Y. Cell. 1998; Full Full PubMed Scopus Google Scholar, A. J. T. Prives C. J. Nakatani Y. Mol. Cell. 1998; 2: Full Full PubMed Scopus Google Scholar, M. K. A. J. Biol. 1999; Full Full PubMed Scopus Google Scholar, T. Ogryzko M. R. J. M. R. J. Nakatani Y. Cell. Full Full PubMed Scopus Google Scholar, E. A. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar), and p400 with the and p400 complexes but not the complex (13Fuchs M. Gerber J. Drapkin R. Sif S. Ikura T. Ogryzko V. Lane W.S. Nakatani Y. Livingston D.M. Cell. 2001; 106: 297-307Abstract Full Full PubMed Scopus Google Scholar). Although it to E1A interacts with a of these the and complexes been in Notably, ARF is not to S.W. Sherr C.J. Curr. Opin. Genet. Dev. 2003; 13: 77-83Crossref PubMed Scopus (616) Google Scholar), and has an in normal cellular it is that of p400-TRRAP chromatin to promote and, or apoptosis. with this p400 complexes possess chromatin remodeling through with by and at of lesions T. R.L. J.L. 2004; PubMed Scopus Google Scholar). mutations and apoptosis. expression of increases apoptosis T. Ogryzko M. R. J. M. R. J. Nakatani Y. Cell. Full Full PubMed Scopus Google Scholar, E. A. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). p400 also as a regulator of cellular by the cyclin-dependent kinase inhibitor M. Lowe S.W. Livingston D.M. Genes Dev. PubMed Scopus Google Scholar), in turn, can apoptosis J. Nature. 2004; 432: PubMed Scopus Google Scholar). by p400 E1A allow complexes to thereby the cellular cell cycle to apoptosis. this the of complexes by a of p400 complex both the in p400 levels and the of by the of the p400 complex by in a that by the it is that the act in E1A target both proteins to efficiently promote cell death. with these in has p400-TRRAP and Rb in cell C.J. Dev. Cell. 2004; Full Full PubMed Scopus Google Scholar). These ultimately cellular E1A in binding p400 or Rb p53 and promote apoptosis in A.V. Lowe S.W. S. A. PubMed Scopus Google Scholar). these cooperate to promote apoptosis in activities for apoptosis, or to apoptotic Although E1A target involved in apoptosis, its to control ARF expression is important for this Stanchina E. McCurrach M.E. Zindy F. Shieh S.Y. Ferbeyre G. Samuelson A.V. Prives C. Roussel M.F. Sherr C.J. Lowe S.W. Genes Dev. 1998; 12: 2434-2442Crossref PubMed Scopus (546) Google Scholar). Although ARF is an E2F target it E2F in that it is not cell cycle is it in S.W. Cepero E. Evan G. Nature. 2004; 432: 307-315Crossref PubMed Scopus (1056) Google Scholar). in mice that ARF is normal signals but to F. Cleveland J.L. Roussel M.F. Sherr C.J. S. A. 2003; PubMed Scopus Google Scholar). component of this a E2F family that is to the ARF promoter in normal cells and is with E2Fs oncogene expression A. Iaquinta P.J. Verona R. Lees J.A. Genes Dev. 2004; 18: 1413-1422Crossref PubMed Scopus (152) Google Scholar). component the protein which at the of higher order chromatin to ARF expression in vitro and in (7Jacobs J.J. Scheijen B. Voncken J.W. Kieboom K. Berns A. van Lohuizen M. Genes Dev. 1999; 13: 2678-2690Crossref PubMed Scopus (539) Google Scholar). identify p400 and its complexes as an additional regulator of the ARF for these is that p400 complexes contribute to the chromatin of the ARF locus, that binding by E1A this a complex that to ARF Consequently, the E1A interaction with of ARF a chromatin that E2Fs to stimulate ARF a or to but p400 with Rb loss to E1A effects. results in of the transcriptional co-activators as critical for E1A to p53 and promote apoptosis. These that E1A at binding to p53 or promote apoptosis J.S. K. Oncogene. 1994; Google Scholar, M. S. Oncogene. 1995; Google Scholar, E. J. PubMed Google Scholar, A.V. Lowe S.W. S. A. PubMed Scopus Google Scholar, E. J. PubMed Google and that overexpression of p300 in E1A-expressing cells p53 and apoptosis A. E. Genes Dev. 1998; 12: PubMed Scopus Google Scholar). the regions of E1A for binding and p400 and not used that the two that an E1A of binding p300 but not p400 is at ARF, p53, and apoptosis also Ref. M. J. 2004; PubMed Scopus Google conversely, of binding p400 but not that these activities and whereas p300 can p53 levels and M. M. C. S. Livingston D.M. Mol. Cell. 1998; 2: Full Full PubMed Scopus Google Scholar, A. E. Genes Dev. 1998; 12: PubMed Scopus Google Scholar), this is not the through which E1A p53 and promotes apoptosis in normal cells. the interaction contribute to apoptosis in to its to act as a p53 transcriptional M. Eckner R. Livingston D. J. PubMed Google Scholar, Nature. PubMed Scopus Google Scholar). tumor to target in cellular signaling and, been widely used to identify cellular activities involved in normal growth For example, using E1A Rb as an important tumor E2F as a component of cell cycle and p53 as a of apoptosis Refs. A.V. Lowe S.W. S. A. PubMed Scopus Google Scholar, S.W. Genes Dev. 7: PubMed Scopus Google Scholar, and E. C. Mol. Cell. Biol. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, M. E. Genes Dev. 7: PubMed Scopus Google Scholar). Although the of p400 to the apoptotic that tumorigenesis to that its this it is that a cellular oncogene that also the ARF-p53 pathway to promote apoptosis, binds and induces p400 protein and requires a p400 complex to promote transformation M. Lowe S.W. Livingston D.M. Genes Dev. PubMed Scopus Google Scholar). in fibroblasts not proapoptotic oncogenes, p400 act to control cellular in part, by the cyclin-dependent kinase inhibitor M. Lowe S.W. Livingston D.M. Genes Dev. PubMed Scopus Google Scholar). these that complexes act as a in that couple apoptosis, and transformation and that can by a transforming of the and of these complexes further the innate tumor suppressor mechanisms that couple proliferation to cell death and transformation.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m414564200