Affiliation:
1. Howard Hughes Medical Institute
2. Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, Tennessee 38105
Abstract
ABSTRACT
The hematopoietic zinc finger protein, Hzf, is induced in response to genotoxic and oncogenic stress. The Hzf protein is encoded by a p53-responsive gene, and its overexpression, either in cells retaining or lacking functional 53, halts their proliferation. Enforced expression of Hzf led to the appearance of tetraploid cells with supernumerary centrosomes and, ultimately, to cell death. Eliminating
Hzf
mRNA expression by use of short hairpin (sh) RNAs had no overt effect on unstressed cells but inhibited the maintenance of G
2
phase arrest following ionizing radiation (IR), thereby sensitizing cells to DNA damage. Canonical p53-responsive gene products such as p21
Cip1
and Mdm2 were induced by IR in cells treated with Hzf shRNA. However, the reduction in the level of Hzf protein was accompanied by increased polyubiquitination and turnover of p21
Cip1
, an inhibitor of cyclin-dependent kinases whose expression contributes to maintaining the duration of the G
2
checkpoint in cells that have sustained DNA damage. Thus, two p53-inducible gene products, Hzf and p21
Cip1
, act concomitantly to enforce the G
2
checkpoint.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
29 articles.
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