VCP/p97 targets the nuclear export and degradation of p27Kip1 during G1 to S phase transition

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

View graph of relations

Detail(s)

Original languageEnglish
Pages (from-to)5193-5207
Journal / PublicationFASEB Journal
Volume34
Issue number4
Online published17 Feb 2020
Publication statusPublished - Apr 2020

Abstract

One of the critical regulatory mechanisms for cell cycle progression is the timely degradation of CDK inhibitors, including p21Cip1 and p27Kip1. VCP/p97, an AAA-ATPase, is reported to be overexpressed in many types of cancers. Here, we found that treatment of MCF-7 human breast cancer cells with DBeQ, a VCP inhibitor, or VCP knockdown in MCF-7 cells arrested cells at G1 phase, accompanied with the blockage of both p21 and p27 degradation. Whereas, double knockdown of p21 and p27 in MCF-7 cells rendered cells refractory to DBeQ-induced G1 arrest. Moreover, inhibition or knockdown of VCP or UFD1, one of VCP's co-factors, in MCF-7, NIH3T3, or HEK293T cells blocked the nuclear export of p27 during earlier G1 phase after mitogen stimulation. We also identified the nuclear localization sequence (NLS) of VCP, and found that adding back wild-type VCP, not the NLS-deleted VCP mutant, restored the nuclear export and degradation of p27 in VCP knockout MCF-7 cells. Importantly, we found that VCP inhibition sensitized breast cancer cells to the treatment of several anticancer therapeutics both in vitro and in vivo. Taken together, our study not only uncovers the mechanisms underlying VCP-mediated cell proliferation control but also provides potential therapeutic option for cancer treatment.

Research Area(s)

  • cell cycle, p21Cip1, p27Kip1, UFD1, VCP/p97