Expression of the HPV E7 oncoprotein mimics but does not evoke a p53-dependent cellular DNA damage response pathway.
Acute expression of the human papillomavirus E7 oncoprotein in preimmortal human fibroblasts induces changes in the abundances of multiple cellular regulatory proteins. These alterations include a destabilization of the retinoblastoma tumor suppressor protein pRB, stabilization of the tumor suppressor protein p53, and increases in the level of the cyclin-dependent kinase inhibitor p21(cip1). Since the HPV E7 oncoproteins can interfere with several cell cycle checkpoints and similar alterations in the levels of pRB, p53, and p21(cip1) are also observed in a p53-dependent response to DNA damage, we investigated whether E7 expression triggers this signal transduction pathway. The results demonstrate that E7-mediated destabilization of pRB does not require p53 activity and is independent of the ability of E7 to induce apoptosis. Moreover, E7-mediated increases in p21(cip1) levels are largely p53-independent and involve stabilization of the p21(cip1) protein. In contrast the decreases in pRB expression in response to DNA damage involve transcriptional downregulation of RB gene expression.
Jones
D L
DL
Harvard Center for Cancer Biology, Massachusetts General Hospital, Boston, Massachusetts, 02115, USA.
Thompson
D A
DA
Suh-Bürgmann
E
E
Grace
M
M
Münger
K
K
D017209:Apoptosis; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage; D015870:Gene Expression; D006801:Humans; D018716:Molecular Mimicry; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis* / Q000235:genetics; D027383:Papillomaviridae / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16