The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth.
E7 is the main transforming protein of human papilloma virus type 16 (HPV16) which is implicated in the formation of cervical cancer. The transforming activity of E7 has been attributed to its interaction with the retinoblastoma (Rb) tumour suppressor. However, Rb binding is not sufficient for transformation by E7. Mutations within a zinc finger domain, which is dispensable for Rb binding, also abolish E7 transformation functions. Here we show that HPV16 E7 associates with histone deacetylase in vitro and in vivo, via its zinc finger domain. Using a genetic screen, we identify Mi2beta, a component of the recently identified NURD histone deacetylase complex, as a protein that binds directly to the E7 zinc finger. A zinc finger point mutant which is unable to bind Mi2beta and histone deacetylase but is still able to bind Rb fails to overcome cell cycle arrest in osteosarcoma cells. Our results suggest that the binding to a histone deacetylase complex is an important parameter for the growthpromoting activity of the human papilloma virus E7 protein. This provides the first indication that viral oncoproteins control cell proliferation by targeting deacetylation pathways.
Brehm
A
A
Wellcome/CRC Institute for Developmental and Cancer Biology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Nielsen
S J
SJ
Miska
E A
EA
McCance
D J
DJ
Reid
J L
JL
Bannister
A J
AJ
Kouzarides
T
T
D000251:Adenosine Triphosphatases; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D004265:DNA Helicases; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000378:metabolism; D016335:Zinc Fingers
D001324:Autoantigens; C115323:CHD4 protein, human; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; C059731:oncogene protein E7, Human papillomavirus type 16; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D000251:Adenosine Triphosphatases; D004265:DNA Helicases