Hdm2在過氧化氫所誘發的細胞老化中之角色探討
The role of Hdm2 in H2O2-induced senescence in WI38 human diploid fibroblast
Date Issued
2005
Date
2005
Author(s)
Su, Shin-Tang
DOI
en-US
Abstract
Cellular senescence, an extremely stable form of cell cycle arrest that serve as a general cellular stress response program. Although diverse stress can induce a senescence response, they appear to be governed by the two tumor suppressor proteins, p53 and pRB. In senescent cell, Rb promotes a distinct heterochromatic structure formation, called senescence associated heterochromatin foci (SAHF). Several E2F target genes that promote cellular proliferation were repressed by packaging into SAHF in senescent cells. The human oncoprotein Mdm2 (Hdm2), a RING domain E3 ubiquitin ligase known as the major negative regulator of p53, also interact with pRB physically. Hdm2 may serve as a mediator between p53 and pRB in senescence response.
In this study, we optimize an effective H2O2-induced senescence protocol and study the role of Hdm2 in H2O2-induced senescence. After treated cell with H2O2, p53 pathways were activated with upregulate Hdm2 protein. Both p53 and Hdm2 are upregulated and sustained during the course of H2O2-induced senescence. The upregulated Hdm2 form the distinct nuclear foci and the ratio of Hdm2 foci is correlated to the ratio of SA-β-gal positive cells in different treatment protocols. Furthermore, H2O2 treatment promotes physical interaction between Hdm2 and Rb. We also find mono-ubiquitylation of histone H4 at second day under 2 × H2O2 treatment. Hdm2 foci formation may be a novel mechanism for p53 sustained activity during H2O2-induced senescence and a possible connection to Rb-dependent SAHF formation.
Subjects
細胞老化
Hdm2
senescence
Type
other