High Risk and Cutaneous Types of HPV Suppress p130 to Induce Host Cell Cycle

Abstract

p130, also known as retinoblastoma like protein 2 (RBL2), is a member of the pocket protein family that is rarely mutated in human tumours. Its expression is largely G0 restricted and posttranscriptionally regulated. We previously demonstrated that E6/E7 oncoproteins encoded by HPV type 16, a high-risk type for cervical cancer progression, must target p130 in order to promote the host cell to exit the quiescence (G0) state and enter the S phase of the cell cycle. P130 is also associated with the DREAM (DP, RB-like, E2F and MuvB) complex in G0/G1, which prevents S phase development by repressing transcription of E2F-regulated genes. In this chapter,  we have used p130 mutants deficient in binding the E7 LXCXE domain (p130mE7), unphosphorylatable by CDK2 (p130PM22) or a combination of both (p130PM22/mE7) to investigate these mechanisms used by E7 proteins to disrupt the p130-DREAM complex and promote cell cycle progression. As HPV16 E7 was unable to suppress p130mE7 but could do so with p130PM22, we discovered that binding of HPV16 E7 to p130 through its LXCXE domain was definitely necessary to disrupt p130-DREAM and promote S phase of the cell cycle. In comparison, the E7 protein encoded by HPV 48 E7, a cutaneous HPV type lacking a functional LXCXE domain, was also capable of disrupting p130-DREAM to promote cell cycling, but via a different mechanism. Thus, HPV48 E7 could suppress a cell cycle block induced by p130mE7 but not p130PM22. Overall, these findings suggest that p130 suppression is needed for HPV-induced cell cycling, and that different HPV E7 proteins can achieve this through various mechanisms.