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PMID: 12138191 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Human papillomavirus oncoprotein E6 inactivates the transcriptional coactivator human ADA3.

Molecular and cellular biology ·Vol. 22 ·No. 16 ·2002-08-00 ·Pages 5801-12

Kumar A, Zhao Y, Meng G, Zeng M, Srinivasan S, Delmolino LM, Gao Q, Dimri G, Weber GF, Wazer DE, Band H, Band V

Abstract

High-risk human papillomaviruses (HPVs) are associated with carcinomas of the cervix and other genital tumors. The HPV oncoprotein E6 is essential for oncogenic transformation. We identify here hADA3, human homologue of the yeast transcriptional coactivator yADA3, as a novel E6-interacting protein and a target of E6-induced degradation. hADA3 binds selectively to the high-risk HPV E6 proteins and only to immortalization-competent E6 mutants. hADA3 functions as a coactivator for p53-mediated transactivation by stabilizing p53 protein. Notably, three immortalizing E6 mutants that do not induce direct p53 degradation but do interact with hADA3 induced the abrogation of p53-mediated transactivation and G(1) cell cycle arrest after DNA damage, comparable to wild-type E6. These findings reveal a novel strategy of HPV E6-induced loss of p53 function that is independent of direct p53 degradation. Given the likely role of the evolutionarily conserved hADA3 in multiple coactivator complexes, inactivation of its function may allow E6 to perturb numerous cellular pathways during HPV oncogenesis.

MeSH Terms
Antineoplastic Agents/pharmacology Cell Cycle/drug effects,physiology Cell Line Cell Transformation, Neoplastic Doxorubicin/pharmacology Genes, Reporter Humans Oncogene Proteins, Viral/genetics,metabolism Papillomaviridae/metabolism Protein Binding Recombinant Fusion Proteins/genetics,metabolism Repressor Proteins/genetics,metabolism Tissue Distribution Transcription Factors/genetics,metabolism Transcription, Genetic Transcriptional Activation Tumor Suppressor Protein p53/genetics,metabolism Two-Hybrid System Techniques
Chemicals
Antineoplastic Agents E6 protein, Human papillomavirus type 16 Oncogene Proteins, Viral Recombinant Fusion Proteins Repressor Proteins TADA3 protein, human Transcription Factors Tumor Suppressor Protein p53 Doxorubicin
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Kumar Ajay
Division of Radiation and Cancer Biology, Department of Radiation Oncology, New England Medical Center, Boston, Massachusetts 02111, USA.
Zhao Yongtong
Meng Gaoyuan
Zeng Musheng
Srinivasan Seetha
Delmolino Laurie M
Gao Qingshen
Dimri Goberdhan
Weber Georg F
Wazer David E
Band Hamid
Band Vimla
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.22.16.5801-5812.2002
Published
2002-08-00
Pages
5801-12
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC133989
Subset
IM
Grants
NCI NIH HHS · R01 CA087986 · United States
NCI NIH HHS · CA70195 · United States
NCI NIH HHS · CA81076 · United States
NCI NIH HHS · CA75075 · United States
NCI NIH HHS · CA76118 · United States
NCI NIH HHS · R01 CA081076 · United States
NCI NIH HHS · CA87986 · United States
External Links
PubMed source DOI: 10.1128/MCB.22.16.5801-5812.2002 PMC Full Text View journal details
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