The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth

Abstract

A.Brehm, S.J.Nielsen and E.A.Miska contributed equally to this work 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 Mi2β, 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 Mi2β 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.

Conserved region 2 of adenovirus E1A has a function distinct from pRb binding required to prevent cell cycle arrest by p16INK4a or p27Kip1

“…A potential candidate for`X' could be HDAC-1, a histone deacetylase recently shown to co-operate with pRb in repressing E2F activity (Brehm et al, 1998;Ferreira et al, 1998;Luo et al, 1998;. Interestingly, the carboxy-terminal Zinc ®nger of HPV16 E7 binds HDAC-1 via a protein called Mi2, independently of pRb (Brehm et al, 1999). A mutant of E7 (L67R) that does not bind Mi2/ HDAC (but still associates with pRb via its LxCxE motif) is defective in preventing arrest by either pRb (Brehm et al, 1999) or p16 (K Alevizopoulos and B Amati, unpublished).…”

“…Interestingly, the carboxy-terminal Zinc ®nger of HPV16 E7 binds HDAC-1 via a protein called Mi2, independently of pRb (Brehm et al, 1999). A mutant of E7 (L67R) that does not bind Mi2/ HDAC (but still associates with pRb via its LxCxE motif) is defective in preventing arrest by either pRb (Brehm et al, 1999) or p16 (K Alevizopoulos and B Amati, unpublished). However, we failed to detect any interaction between HDAC-1 and E1A in Rat1 cells (data not shown).…”

Viral epigenomes in human tumorigenesis

“…Apart from methylation changes in this virus genome, other epigenetic changes might occur through direct interactions between HPV proteins (E2, E7) and cell proteins involved in DNA methylation (DNMT1) (Burgers et al, 2006), or through processes related to the chromatin remodeling machinery (CBP, pCAF, p300, Mi2b) (Brehm et al, 1999;Patel et al, 1999;Lee et al, 2000;Peng et al, 2000;Avvakumov et al, 2003;Bernat et al, 2003), eventually modifying the normal epigenetic processes in the host.…”

Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins

“…If this region is involved or not in the binding of E7 with the RB family proteins is controversial (McIntyre et al, 1993;Patrick et al, 1994), but it is definitely involved in the interference with several important cellular factors, as the AP1 transcriptional machinery, HDAC-1, pCAF and BRCA1 (Antinore et al, 1996;Brehm et al, 1999;Park et al, 2000;Avvakumov et al, 2003;Zhang et al, 2005).…”