title: The ability of E1A to rescue ras-induced premature senescence and confer transformation relies on inactivation of both p300/CBP and Rb family proteins.
abstract: In primary cells, oncogenic ras induces a stable growth arrest known as premature senescence. Ras-induced premature senescence is considered as a tumor-suppressing defense response that needs to be bypassed before oncogenic potential ras can be revealed. To gain insights into the mechanism of senescence bypass during oncogenic transformation, we dissected the activities of an adenoviral oncoprotein E1A, which is capable of overcoming ras-induced senescence. Our results have indicated that the senescence bypassing activity resides in the NH2 terminus and requires both Rb-binding and p300/CBP-binding functions of E1A. Although interference with the p16(INK4A)/Rb pathway or inactivation of p300/CBP alone did not lead to senescence bypass, these two types of genetic alterations complemented the Rb-binding defective and the p300/CBP-binding defective mutants of E1A, respectively, to rescue premature senescence. Therefore, genetic alterations disrupting the p16(INK4A)/Rb pathway or the p300/CBP functions both contribute to the bypass of senescence. We further showed that p300/CBP were essential for ras-induced p53 activity, providing a potential mechanism underlying the important role of p300/CBP in senescence. Furthermore, p300/CBP inactivation led to cellular transformation in cooperation with the p300/CBP-binding defective E1A mutants, MDM2 and Ha-RasV12. These results have shown that p300 and CBP are integral components of the pathway that mediates ras-induced senescence. The critical role of p300 and CBP in the senescence response that limits the oncogenic potential of ras has provided a mechanistic basis for the tumor-suppressing function of these proteins.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 91037, USA.
authors.forename: Qingdong
authors.initials: Q
authors.lastname: Deng
authors.forename: Yilei
authors.initials: Y
authors.lastname: Li
authors.forename: Donato
authors.initials: D
authors.lastname: Tedesco
authors.forename: Rong
authors.initials: R
authors.lastname: Liao
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fuhrmann
authors.forename: Peiqing
authors.initials: P
authors.lastname: Sun
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004265:DNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D017500:Adenovirus E1A Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D050880:p300-CBP Transcription Factors; D004265:DNA Helicases; C498558:EP400 protein, human