p53 Homologue p63 Represses Epidermal Growth Factor Receptor Expression

Abstract

Tumor suppressor p53 has been shown to transactivate epidermal growth factor receptor (EGFR) expression through binding to a putative p53 responsive element in the EGFR promoter between nucleotides −265 and −239 (EGFRp53RE). Isotypes of p63 gene products, recently identified as p53 relatives, have a similar function to transactivate several p53 target gene promoters. However, our results indicate that TAp63γ has a very low ability to bind to the EGFRp53RE and surprisingly represses both basal EGFR promoter activity and endogenous EGFR expression. Transient transfection assays show that the EGFR promoter region between −348 and −293, containing two Sp1 sites, is crucial for the repression of the EGFR expression by TAp63γ. Mutations in these Sp1 sites in the reporter constructs result in loss of the TAp63γ repression effect. We further show that TAp63γ directly interacts with Sp1 by immunoprecipitation analysis and that TAp63γ impairs Sp1 binding to the target DNA site in electrophoretic mobility shift assays. These results suggest that TAp63γ is involved in the regulation of the EGFR gene expression through interactions with basal transcription factors. Tumor suppressor p53 has been shown to transactivate epidermal growth factor receptor (EGFR) expression through binding to a putative p53 responsive element in the EGFR promoter between nucleotides −265 and −239 (EGFRp53RE). Isotypes of p63 gene products, recently identified as p53 relatives, have a similar function to transactivate several p53 target gene promoters. However, our results indicate that TAp63γ has a very low ability to bind to the EGFRp53RE and surprisingly represses both basal EGFR promoter activity and endogenous EGFR expression. Transient transfection assays show that the EGFR promoter region between −348 and −293, containing two Sp1 sites, is crucial for the repression of the EGFR expression by TAp63γ. Mutations in these Sp1 sites in the reporter constructs result in loss of the TAp63γ repression effect. We further show that TAp63γ directly interacts with Sp1 by immunoprecipitation analysis and that TAp63γ impairs Sp1 binding to the target DNA site in electrophoretic mobility shift assays. These results suggest that TAp63γ is involved in the regulation of the EGFR gene expression through interactions with basal transcription factors. epidermal growth factor receptor transactivation type of p63 subtype γ δN terminus stimulatory protein 1 p53 response element luciferase mutant hemagglutinin thymidine kinase 3-(N-morpholino)propanesulfonic acid The epidermal growth factor receptor (EGFR)1 plays an important role in cell growth and development (1Carpenter G. Annu. Rev. Biochem. 1987; 56: 881-914Crossref PubMed Scopus (1053) Google Scholar, 2Merlino G.T. Semin. Cancer Biol. 1990; 1: 277-284PubMed Google Scholar, 3Hernandez-Sotomayor S.M. Carpenter G. J. Membr. Biol. 1992; 128: 81-89Crossref PubMed Scopus (82) Google Scholar). Overexpression of the EGFR can lead to epidermal growth factor-dependent transformation (4Velu T.J. Beguinot L. Vass W.C. Willingham M.C. Merlino G.T. Pastan I. Lowy D.R. Science. 1987; 238: 1408-1410Crossref PubMed Scopus (352) Google Scholar, 5Di Fiore P.P. Pierce J.H. Fleming T.P. Hazan R. Ullrich A. King C.R. Schlessinger J. Aaronson S.A. Cell. 1987; 51: 1063-1070Abstract Full Text PDF PubMed Scopus (508) Google Scholar). High levels of the EGFR have been detected in several types of cancers such as glioblastomas due to gene amplification (6King C.R. Kraus M.H. Williams L.T. Merlino G.T. Pastan I.H. Aaronson S.A. Nucleic Acids Res. 1985; 13: 8477-8486Crossref PubMed Scopus (81) Google Scholar). Overexpression of EGFR transcripts in a variety of tumors such as ovarian, cervical, and kidney tumors results from transcriptional or post-transcriptional mechanisms (7Xu Y.H. Richert N. Ito S. Merlino G.T. Pastan I. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 7308-7312Crossref PubMed Scopus (208) Google Scholar). Also, a variety of agents have been shown to increase EGFR gene expression (8Hou X. Johnson A.C. Rosner M.R. Cell Growth Differ. 1994; 5: 801-809PubMed Google Scholar, 9Hudson L.G. Thompson K.L. Xu J. Gill G.N. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 7536-7540Crossref PubMed Scopus (55) Google Scholar, 10Hudson L.G. Gill G.N. Genet. Eng. 1991; 13: 137-151Crossref Scopus (7) Google Scholar). Repression of EGFR gene transcription by different agents has been also reported (11Hudson L.G. Santon J.B. Glass C.K. Gill G.N. Cell. 1990; 62: 1165-1175Abstract Full Text PDF PubMed Scopus (109) Google Scholar, 12Zheng Z.S. Polakowska R. Johnson A. Goldsmith L.A. Cell Growth Differ. 1992; 3: 225-232PubMed Google Scholar). Thus, transcriptional control plays a major role in regulation of EGFR gene expression. The promoter of the EGFR gene lacks a TATA box and CAAT box but contains multiple GC boxes and multiple transcription initiation sites. A number of regions in the promoter have been identified that bind nuclear factors (13Johnson A.C. Ishii S. Jinno Y. Pastan I. Merlino G.T. J. Biol. Chem. 1988; 263: 5693-5699Abstract Full Text PDF PubMed Google Scholar, 14Johnson A.C. Jinno Y. Merlino G.T. Mol. Cell. Biol. 1988; 8: 4174-4184Crossref PubMed Scopus (119) Google Scholar, 15Chen L.L. Clawson M.L. Bilgrami S. Carmichael G. Cell Growth Differ. 1993; 4: 975-983PubMed Google Scholar). Four repressor proteins, EGFR transcriptional repressor, GC-binding factor, GC-binding factor 2, and the Wilms’ tumor suppressor bind to sites within the EGFR promoter (16Hou X. Johnson A.C. Rosner M.R. J. Biol. Chem. 1994; 269: 4307-4312Abstract Full Text PDF PubMed Google Scholar, 17Kageyama R. Pastan I. Cell. 1989; 59: 815-825Abstract Full Text PDF PubMed Scopus (207) Google Scholar, 18Reed A.L. Yamazaki H. Kaufman J.D. Rubinstein Y. Murphy B. Johnson A.C. J. Biol. Chem. 1998; 273: 21594-21602Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 19Englert C. Hou X. Maheswaran S. Bennett P. Ngwu C. Re G.G. Garvin A.J. Rosner M.R. Haber D.A. EMBO J. 1995; 14: 4662-4675Crossref PubMed Scopus (311) Google Scholar). Sp1, interferon-regulated factor-1, EGFR transcription factor, activator protein-1, and activator protein-2 have been shown to increase EGFR gene transcription (20Kageyama R. Merlino G.T. Pastan I. J. Biol. Chem. 1988; 263: 6329-6336Abstract Full Text PDF PubMed Google Scholar, 21Rubinstein Y.R. Proctor K.N. Bergel M. Murphy B. Johnson A.C. FEBS Lett. 1998; 431: 268-272Crossref PubMed Scopus (18) Google Scholar, 22Kageyama R. Merlino G.T. Pastan I. J. Biol. Chem. 1989; 264: 15508-15514Abstract Full Text PDF PubMed Google Scholar, 23Johnson A.C. Murphy B.A. Matelis C.M. Rubinstein Y. Piebenga E.C. Akers L.M. Neta G. Vinson C. Birrer M. Mol. Med. 2000; 6: 17-27Crossref PubMed Google Scholar, 24Johnson A.C. J. Biol. Chem. 1996; 271: 3033-3038Abstract Full Text Full Text PDF PubMed Google Scholar). Two groups have shown that p53 can transactivate EGFR via binding to an upstream site of the EGFR promoter between −265 and −239 base pairs (25Ludes-Meyers J.H. Subler M.A. Shivakumar C.V. Munoz R.M. Jiang P. Bigger J.E. Brown D.R. Deb S.P. Deb S. Mol. Cell. Biol. 1996; 16: 6009-6019Crossref PubMed Scopus (156) Google Scholar, 26Sheikh M.S. Carrier F. Johnson A.C. Ogdon S.E. Fornace A.J. Oncogene. 1997; 15: 1095-1101Crossref PubMed Scopus (40) Google Scholar). p53 is the most frequently mutated tumor suppressor gene identified thus far in human cancers (27Hollstein M. Sidransky D. Vogelstein B. Harris C.C. Science. 1991; 253: 49-53Crossref PubMed Scopus (7460) Google Scholar, 28Levine A.J. Momand J. Finlay C.A. Nature. 1991; 351: 453-456Crossref PubMed Scopus (3658) Google Scholar). p53 appears to induce cell cycle arrest or apoptosis in response to cellular stresses such as DNA damage, mitotic spindle misassembly, and hypoxia. The actions are mediated through transcriptional regulation of p53 target genes (29El-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. D. Vogelstein B. Cell. 1993; Full Text PDF PubMed Scopus Google A.J. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). of p53 activity as a transcription p53 to binding of the by base and expression of target genes W.S. S. Vogelstein B. Genet. 1992; 1: PubMed Scopus Google Scholar). genes to and to to p53 are (29El-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. D. Vogelstein B. Cell. 1993; Full Text PDF PubMed Scopus Google Y. T. R. M. EMBO J. 1993; PubMed Scopus Google W.S. Carrier F. T. Vogelstein B. Fornace A.J. Cell. 1992; Full Text PDF PubMed Scopus Google T. Cell. 1995; Full Text PDF PubMed Scopus Google cell nuclear C.V. Brown D.R. Deb S. Deb S.P. Mol. Cell. Biol. 1995; 15: PubMed Scopus Google and D. EMBO J. 1994; 13: PubMed Scopus Google Scholar). The p53 in human cancers are in the of the p53 M.S. Bennett M. Harris C.C. Cancer Res. 1994; Google Scholar). to an of p53 function through of DNA binding and p53 as a tumor loss of function appears to to through growth and to cell C. T. A.J. Nature. 1996; PubMed Scopus Google Vogelstein B. Nature. 1996; PubMed Scopus Google Scholar). Two genes that are to with acid to p53 have been recently identified M. H. A. L. A. A. P. J.M. X. P. F. D. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, C.A. M.C. Nature. 1997; PubMed Scopus Google Scholar, M. M. C. C. R. I. Y. Y. A. M. S. Med. 1998; 4: PubMed Scopus Google Scholar, A. M. Y. Fleming D. F. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, M. N. M. S. M. S. T. M. T. Y. H. Biochem. Res. 1998; PubMed Scopus (119) Google Scholar, B. L. J. Sidransky D. Med. 1998; 4: PubMed Scopus Google Scholar, M. C. D. H. 1998; PubMed Scopus Google Scholar, L.A. P. C.A. A. Kaufman T.P. Full Text Full Text PDF PubMed Scopus Google Scholar). of the p53 acid that are in DNA binding is in these M. H. A. L. A. A. P. J.M. X. P. F. D. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, C.A. M.C. Nature. 1997; PubMed Scopus Google Scholar, M. M. C. C. R. I. Y. Y. A. M. S. Med. 1998; 4: PubMed Scopus Google Scholar, A. M. Y. Fleming D. F. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, M. N. M. S. M. S. T. M. T. Y. H. Biochem. Res. 1998; PubMed Scopus (119) Google Scholar, B. L. J. Sidransky D. Med. 1998; 4: PubMed Scopus Google Scholar, M. C. D. H. 1998; PubMed Scopus Google Scholar, L.A. P. C.A. A. Kaufman T.P. Full Text Full Text PDF PubMed Scopus Google Scholar). of these is to and a protein with to p53 M. H. A. L. A. A. P. J.M. X. P. F. D. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). the transcription of and also apoptosis in a M. H. A. L. A. A. P. J.M. X. P. F. D. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, C.A. M.C. Nature. 1997; PubMed Scopus Google Scholar). to the of M. M. C. C. R. I. Y. Y. A. M. S. Med. 1998; 4: PubMed Scopus Google Scholar, A. M. Y. Fleming D. F. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, M. N. M. S. M. S. T. M. T. Y. H. Biochem. Res. 1998; PubMed Scopus (119) Google Scholar, B. L. J. Sidransky D. Med. 1998; 4: PubMed Scopus Google Scholar, M. C. D. H. 1998; PubMed Scopus Google Scholar, L.A. P. C.A. A. Kaufman T.P. Full Text Full Text PDF PubMed Scopus Google Scholar). the acid and the reported to have to from a gene A. M. Y. Fleming D. F. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). have been reported of of the are type and with DNA and similar to The the are and have different that are as and γ A. M. Y. Fleming D. F. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, the types are and TAp63γ and the types are and TAp63γ has the terminus and the to induce apoptosis and growth in a similar to The is through the p53 element and cellular similar to by p53 M. M. C. C. R. I. Y. Y. A. M. S. Med. 1998; 4: PubMed Scopus Google Scholar, A. M. Y. Fleming D. F. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). TAp63γ several identified p53 target gene such as and M. M. C. C. R. I. Y. Y. A. M. S. Med. 1998; 4: PubMed Scopus Google Scholar, A. S. M. Y. M. R. S. C. Cancer Res. 59: Google Scholar). Thus, is to a tumor suppressor gene and as an tumor suppressor gene expression is by the loss of p53 function M. M. C. C. R. I. Y. Y. A. M. S. Med. 1998; 4: PubMed Scopus Google Scholar). the that are with the terminus or the terminus are to A. M. Y. Fleming D. F. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). These also in a both p53 and of p63 through the reporter containing multiple of A. M. Y. Fleming D. F. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the transactivation of the EGFR promoter transfection assays and also binding to the EGFR promoter by electrophoretic mobility shift assays. results indicate a for regulation of EGFR gene expression through of with The human cell cell is p53 in with and The human cell is also p53 in with reporter constructs containing the EGFR and by of the promoter from constructs Y.R. Proctor K.N. Bergel M. Murphy B. Johnson A.C. FEBS Lett. 1998; 431: 268-272Crossref PubMed Scopus (18) Google Scholar). The of of the constructs is to the EGFR the to the and contains of the by B. Vogelstein (29El-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. D. Vogelstein B. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). by of the thymidine kinase promoter from by of the from and and from and The by of site from the EGFR promoter the the site site is upstream of the promoter TATA The or has the EGFR promoter region between and with or the Sp1 site as an of p53 The and constructs the as the constructs but are in the EGFR promoter The expression and the p53 with the site to TAp63γ from and of TAp63γ expression reporter gene the the of the EGFR p53 response element and a of are the with and of the or assays of Sp1 site transcriptional activity of with the or and of the TAp63γ expression The of Sp1 site are and and of mutated Sp1 site are and assays indicate in and and in a of expression of DNA in of and a to the The with and to the for of or containing for and for an and with luciferase cell activity in in the luciferase and and with of or constructs TAp63γ terminus with hemagglutinin by the as the to containing to the number of and for in 1 1 containing The for and the with a protein of protein a and to for The a and with and The with the of the EGFR detected by with The of EGFR the of the and and with of or constructs TAp63γ by the as the to containing to the number of and cellular and by an to in the to a in by The to the by with a The with in to the the in containing and containing The with for The from the to the for The p53 and and with proteins, to the regions and for region also and for of DNA in in the of with the from by p53 and TAp63γ in the of of and with mobility shift assays as M.S. Carrier F. Johnson A.C. Ogdon S.E. Fornace A.J. Oncogene. 1997; 15: 1095-1101Crossref PubMed Scopus (40) Google Scholar). a containing the p53 site by two and in a containing and 1 of the in a and in a The to to and the a The with kinase and electrophoretic mobility shift the with of p53 and TAp63γ for in the of a binding and 1 of assays an p53 from or the EGFR promoter with protein and for to the of the binding site as two from and as a and to for 1 and as Sp1 the Sp1 with as The Sp1 and of nuclear with or the in p53 or TAp63γ for in binding or of Sp1 or of with nuclear and the binding for to the of Sp1 to with the as to and to with of nuclear and p53 or in of 1 for Two of and for an 1 with of protein for and in and in a from in and a The and to to p63 gene products, are a similar function EGFR expression. p53 and transactivation of the EGFR the EGFR luciferase with or and to the A. M. Y. Fleming D. F. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google p53 reporter activity A and TAp63γ also TAp63γ surprisingly reporter activity A and A and in luciferase activity with the in and analysis that but reporter activity in a 1 TAp63γ represses endogenous EGFR EGFR and protein levels by the TAp63γ and by and EGFR by in the as with the have expression of EGFR as a control Also, the EGFR protein by in the as with the The of TAp63γ by analysis These results indicate that TAp63γ represses EGFR expression the transcriptional in an endogenous Thus, the represses the EGFR expression. the of within the of the p53 and p63 M. M. C. C. R. I. Y. Y. A. M. S. Med. 1998; 4: PubMed Scopus Google Scholar, A. M. Y. Fleming D. F. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, M. N. M. S. M. S. T. M. T. Y. H. Biochem. Res. 1998; PubMed Scopus (119) Google Scholar, B. L. J. Sidransky D. Med. 1998; 4: PubMed Scopus Google Scholar, M. C. D. H. 1998; PubMed Scopus Google Scholar, L.A. P. C.A. A. Kaufman T.P. Full Text Full Text PDF PubMed Scopus Google is that TAp63γ can bind p53 DNA target sites. We a luciferase has of the site identified in the EGFR promoter upstream of the thymidine kinase TATA region and transactivation and of the with or an p53 to transactivate by TAp63γ also reporter activity A increase in luciferase activity with the results in a a luciferase reporter containing the thymidine kinase promoter TAp63γ or p53 These results that TAp63γ can transactivate the site of EGFR promoter in an TAp63γ with p53 target DNA sites. We p53 and TAp63γ in in as by (25Ludes-Meyers J.H. Subler M.A. Shivakumar C.V. Munoz R.M. Jiang P. Bigger J.E. Brown D.R. Deb S.P. Deb S. Mol. Cell. Biol. 1996; 16: 6009-6019Crossref PubMed Scopus (156) Google that p53 bind the of the site identified in the EGFR promoter M.S. Carrier F. Johnson A.C. Ogdon S.E. Fornace A.J. Oncogene. 1997; 15: 1095-1101Crossref PubMed Scopus (40) Google Scholar). However, binding of TAp63γ to the EGFRp53RE but binding of p53 and TAp63γ to the site and The binding of p53 and TAp63γ to element the binding by of the p53 response element of and the binding by The binding to p53 by of EGFRp53RE and the binding to TAp63γ by EGFRp53RE The and the results of are in these results indicate that p53 to the putative site in the EGFR promoter with low and p63 binding is by our assays. We to the in the EGFR promoter for of the EGFR promoter region to the luciferase gene these with the TAp63γ expression The results show that containing to containing to and containing −348 to to the similar by with and that to and to A similar also in These results suggest that nucleotides between −348 and within the EGFR promoter are for EGFR promoter region crucial for TAp63γ a luciferase has region upstream of a thymidine kinase in reporter and the results that TAp63γ the activity by A similar also the EGFR promoter region between nucleotides −348 and −293, are two sites, and and and (13Johnson A.C. Ishii S. Jinno Y. Pastan I. Merlino G.T. J. Biol. Chem. 1988; 263: 5693-5699Abstract Full Text PDF PubMed Google Scholar). has been shown that Sp1 EGFR promoter activity (13Johnson A.C. Ishii S. Jinno Y. Pastan I. Merlino G.T. J. Biol. Chem. 1988; 263: 5693-5699Abstract Full Text PDF PubMed Google and that Sp1 interacts with p53 and with F. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar, J. T. H. P. A. Oncogene. 1995; Google Scholar, D. A. M. A. G. C. P. Oncogene. 2000; PubMed Scopus Google Scholar, B. D. G. Oncogene. 2000; PubMed Scopus Google Scholar). region to crucial for EGFR repression by TAp63γ bind to region by electrophoretic mobility shift results of TAp63γ with region We the between TAp63γ and the TAp63γ repression activity mediated through sites, mutated these sites in the We the or with TAp63γ or p53 expression TAp63γ activity to a similar as and in the sites repression Also, p53 the activity of reporter TAp63γ p53 to the activity both Sp1 sites results in These results suggest that the sites are for repression of EGFR expression. further the role of region in EGFR promoter in the site and the sites in the These mutant constructs for ability to by p53 and TAp63γ The by p53 but by TAp63γ. The by TAp63γ but by The by p53 as as with of both the p53 and Sp1 sites in loss of p53 and TAp63γ These results that nucleotides between −348 and are for TAp63γ mediated TAp63γ EGFR gene The that that TAp63γ with Sp1 and binding to the Sp1 in the EGFR between Sp1 and TAp63γ with nuclear from and Sp1 to shown in and These results that the TAp63γ activity EGFR promoter mediated through the Sp1 sites and a of binding by TAp63γ through the TAp63γ that have sites, assays these reporter constructs and TAp63γ. of has sites with the or that TAp63γ the contains A and has several sites as as and have Sp1 site or These results indicate that TAp63γ has been reported that p53 impairs Sp1 binding to through F. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar, J. T. H. P. A. Oncogene. 1995; Google Scholar, D. A. M. A. G. C. P. Oncogene. 2000; PubMed Scopus Google Scholar). TAp63γ with Sp1 binding to nuclear and TAp63γ. shown in a of the to Sp1 in nuclear binding by with TAp63γ protein the binding of Sp1 in a similar to the of p53 These results indicate that TAp63γ impairs the binding of Sp1 to the promoter region through with the the of p63 gene in the regulation of EGFR expression. We reporter assays that repression of EGFR promoter activity 1 The results from and that TAp63γ endogenous EGFR expression 2, A and TAp63γ has been shown to transcriptional activity A. M. Y. Fleming D. F. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). such a between p53 and TAp63γ in the regulation of EGFR of reporter assays of the element in the EGFR promoter region The results that TAp63γ transactivate activity to the as p53 EGFRp53RE as a that in to bind to the EGFRp53RE and is p53 and TAp63γ different of DNA binding to the such as and to that binding of p53 and TAp63γ to the EGFRp53RE is and our We by of that the region of repression between nucleotides −348 and have shown that are two sites in region (13Johnson A.C. Ishii S. Jinno Y. Pastan I. Merlino G.T. J. Biol. Chem. 1988; 263: 5693-5699Abstract Full Text PDF PubMed Google Scholar). analysis in these two sites that repression the sites and Sp1 is a basal transcription factor that is involved in the regulation of several important genes T. B. R. N. Y. Acad. Sci. PubMed Scopus Google Scholar). between Sp1 and TAp63γ by immunoprecipitation The results show that TAp63γ with Sp1 as p53 of as as TAp63γ in as a of gene promoters. p53 represses the transcription of and through a can gene transcription F. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar, J. T. H. P. A. Oncogene. 1995; Google Scholar, D. A. M. A. G. C. P. Oncogene. 2000; PubMed Scopus Google Scholar). p53 has been reported to growth factor transcription through with Sp1 binding B. D. G. Oncogene. 2000; PubMed Scopus Google Scholar). These to TAp63γ the ability of Sp1 to bind to the target sites in the EGFR promoter The results that as as Sp1 binding to the target DNA in a to that genes binding in the promoter region and that can as a the promoter lacks binding and is by The results in a that repression by TAp63γ the number of site in the promoter also We have that TAp63γ represses EGFR promoter activity through a that the sites. that the of Sp1 and TAp63γ result in a that the role of Sp1 in EGFR However, interacts with Sp1 with a similar is to EGFR promoter activity through binding to the promoter the in the of a binding p53 to repression of promoter activity to a similar as TAp63γ Thus, the by in EGFR promoter activity are mediated by TAp63γ with Sp1 as Overexpression of EGFR has been in a number of tumors (4Velu T.J. Beguinot L. Vass W.C. Willingham M.C. Merlino G.T. Pastan I. Lowy D.R. Science. 1987; 238: 1408-1410Crossref PubMed Scopus (352) Google Scholar, 5Di Fiore P.P. Pierce J.H. Fleming T.P. Hazan R. Ullrich A. King C.R. Schlessinger J. Aaronson S.A. Cell. 1987; 51: 1063-1070Abstract Full Text PDF PubMed Scopus (508) Google Scholar, C.R. Kraus M.H. Williams L.T. Merlino G.T. Pastan I.H. Aaronson S.A. Nucleic Acids Res. 1985; 13: 8477-8486Crossref PubMed Scopus (81) Google Scholar, Y.H. Richert N. Ito S. Merlino G.T. Pastan I. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 7308-7312Crossref PubMed Scopus (208) Google Scholar). the the regulation of EGFR gene is far the of expression. are for the of EGFR gene are in human results suggest that TAp63γ a as a of EGFR expression. p63 is for and development and a has been in an A. R. D. M. N. C. A. D. C. F. Nature. PubMed Scopus Google Scholar, B. H. D.R. A. Nature. PubMed Scopus Google Scholar, J. P. M. B. R. G. A. A.J. R. G. Haber D.A. A. F. H. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). of the EGFR has been to in development L.M. Biol. 1997; PubMed Google Scholar). the p63 gene as a p53 is frequently mutated in human cancers to M. T. M. S. N. H. S. C. S. Y. A. Oncogene. PubMed Scopus (55) Google Scholar, H. Y. S. A. Ito H. M. H. M. J. 15: Google Scholar, Harris C.C. Cancer Res. 59: Google Scholar, J.H. Cancer Res. 2000; Google Scholar). However, and J.H. Cancer Res. 2000; Google have reported that expression of frequently in but in J.H. Cancer Res. 2000; Google Scholar, B. M. J. Sidransky D. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar, M. I. Y. T. Y. H. T. S. J. PubMed Scopus Google Scholar). have shown that TAp63γ represses EGFR gene expression through a factors with the These that TAp63γ can as a transcriptional repressor of the EGFR suggest an role of TAp63γ in human The ability of TAp63γ to transformation of by EGFR gene and the between TAp63γ and EGFR in human tumors are We Vogelstein and for the