Destabilization ofpRB pl07 andpl30

Binding of the high-risk HPV E7 proteins results in destabilization of pRB, p107, and p130 (Berezutskaya et al., 1997; Boyer et al., 1996; Giarre et al., 2001; Gonzalez et al., 2001; Helt and Galloway, 2001; Jones et al., 1997b; Smith-McCune et al., 1999) via a proteasome-dependent pathway (Boyer et al., 1996; Gonzalez et al., 2001). Interestingly, the pp71 protein of the human cytomegalovirus (CMV) and the Epstein-Barr virus nuclear antigen 3c (EBV EBNA 3C) also induce degradation of pRB family members (Kalejta and Shenk, 2003; Knight et al., 2005). Association of E7 with pRB is necessary but not sufficient for pRB degradation since transformation-defective amino terminal CR1 homology domain E7 mutants efficiently associate with pRB but are defective for pRB degradation (Edmonds and Vousden, 1989; Gonzalez et al., 2001; Helt and Galloway, 2001; Jones et al., 1997b; Phelps et al., 1992) and maintenance of HPV episomes in keratinocytes (Thomas et al., 1999). Similarly, the low-risk HPV1 E7 protein efficiently binds pRB but is unable to destabilize pRB and is transformation-deficient (Giarre et al., 2001; Gonzalez et al., 2001). The ability to destabilize p130 is shared by mucosal high-risk and low-risk HPV E7 proteins, suggesting that this activity contributes to the role of E7 in the viral life cycle (Zhang et al., 2006).

HPV-16 E7 has a short half-life of less than 2 hours (Smotkin and Wettstein, 1987) and is itself degraded through a proteasome-mediated mechanism (Reinstein et al., 2000), potentially involving a cullin 1-containing ubiquitin ligase complex that associates with E7 (Oh et al., 2004a). There is no evidence, however, that E7-induced pRB degradation is linked to ubiquitin-mediated degradation of E7 as a degradation-resistant version of E7 retains the capacity to target pRB for degradation (Gonzalez et al., 2001).

The detailed mechanism that E7 employs to stimulate pRB degradation remains elusive. HPV16 E7 binds the S4 subunit of the 26S proteasome (Berezutskaya and Bagchi, 1998), but S4 binding does not appear necessary for E7-mediated pRB degradation (Gonzalez et al., 2001). Some results suggest that E7 may accelerate pRB degradation through association with a cellular factor. Indeed, ectopic expression of a pRB-binding deficient E7 mutant interferes with pRB destabilization mediated by wild-type E7 (Gonzalez et al., 2001).

The ability of high-risk HPV E7 to destabilize pRB is not shared by the Ad E1A and SV40 T Ag oncoproteins, illustrating that these viruses have developed divergent strategies to inactivate this vital cellular regulatory protein. In the case of SV40 T-antigen an amino terminal J-domain (Kelley and Georgopoulos, 1997) is necessary to inactivate pRB (Sheng et al., 1997; Zalvide et al., 1998) and to alter steady state levels of phosphorylated p107 and p130 (Stubdal et al., 1996, 1997), even though this domain does not directly contribute to pocket protein binding. J-domains are signature sequences of the DnaJ/hsp40 family of proteins, specificity subunits of DnaJ-DnaK chaperone complexes (reviewed by Silver and Way (1993)). HPV16 E7-mediated activation of E2F-responsive promoters may also involve a J-domain protein (Sheng et al., 1997). Although HPV16 E7 does not contain a J-domain, it binds to the cellular DnaJ protein, hTid1 (Schilling et al., 1998).

The ability of HPV E7 to destabilize pocket proteins provides an effective strategy for viral oncoproteins that are expressed at low levels to inactivate cellular target proteins that are expressed at much higher levels. Through reduction of pRB steady state levels these viral oncoproteins can impair the entire spectrum of biological activities of the pocket proteins (Sellers et al., 1998). It is conceivable that the carcinogenic potential of high-risk HPVs may be related, at least in part, to the ability of high-risk HPV E7 proteins to subvert biological activities of pRB other than cell-cycle regulation, such as the ability of the pRB tumor suppressor to regulate differentiation. This activity is unique to pRB and is not shared by p107 and p130, which are not recognized as bona fide human tumor suppressors (Nguyen and McCance, 2005; Thomas et al., 2003). Low-risk HPV E7 proteins do not destabilize pRB and may not be able to modify these putative tumor suppressive activities.

Was this article helpful?

0 0
Joy Of Modern Parenting Collection

Joy Of Modern Parenting Collection

This is a collection of parenting guides. Within this collection you will find the following titles: Issues, rule and discipline, self esteem and tips plus more.

Get My Free Ebook


Post a comment