Star-PAP controls HPV E6 regulation of p53 and sensitizes cells to VP-16

Abstract

Cervical cancer is the most common genital malignancy and the high-risk human papillomaviruses (HPV type 16, 18 and 31, and so on) are major agents for its cause. A key switch for the onset of cervical cancers by HPVs is the cellular degradation of the tumor-suppressor p53 that is mediated by the HPV-generated E6 protein. E6 forms a complex with the E3 ubiquitin-ligase E6-associated protein (E6AP) leading to p53 degradation. The components that control E6 expression and the mechanisms for regulation of the expression in host cells remain undefined. Here we show that the nuclear noncanonical poly(A) polymerase (PAP) speckle targeted PIPKIα regulated PAP (Star-PAP) controls E6 mRNA polyadenylation and expression and modulates wild-type p53 levels as well as cell cycle profile in high-risk HPV-positive cells. In the absence of Star-PAP, treatment of cells with the chemotherapeutic drug VP-16 dramatically reduced E6 and increased p53 levels. This diminished both cell proliferation and anchorage-independent growth required for cancer progression, indicating a synergism between VP-16 treatment and the loss of Star-PAP. This identifies Star-PAP as a potential drug target for the treatment of HPV-positive cancer cells. These data provide a mechanistic basis for increasing the sensitivity and efficiency of chemotherapy in the treatment of cancers that have low levels of wild-type p53.

Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition

“…Note, however, that in HeLa cells, the level of wild-type endogenous p53 is suppressed by human papillomavirus E6, it has been shown that p53 can escape from its E6-mediated down-regulation upon stress in some contexts ( Wesierska-Gadek et al. , 2002 ; Li and Anderson, 2014 ), and our data suggest that treatment with these compounds is also able to restore endogenous p53 levels in the presence of E6 as a long-term effect, further reinforcing the progressive nature of senescence establishment after removal of the compounds.…”

PIP kinases define PI4,5P2 signaling specificity by association with effectors

“…Although the PIPKIα-mediated PI4,5P 2 signaling specifically modulates Star-PAP activity, not all Star-PAP targeting mRNAs are regulated by PIPKIα [183, 195, 202]. It is likely that other nuclear speckle targeted PIP kinases such as PIPKIγi4 or nuclear PIPKII isoforms may control additional Star-PAP target mRNAs.…”

BAG3 down-modulation sensitizes HPV18+ HeLa cells to PEITC-induced apoptosis and restores p53

“…However, the viral E6 oncoprotein strongly affects the p53 status in HPV-infected cells mainly by promoting p53 proteasome degradation [35] and inhibiting its transactivation [36]. The restoration of p53 in high risk HPV + cells has been shown to positively correlate with increased susceptibility to undergo apoptosis in response to chemical and physical agents [37,38]. Regarding PEITC, literature data suggest that the involvement of p53 pathways in PEITC cell growth inhibition is cell type-specific [39][40][41][42][43].…”