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Molecular and Cellular Biology, January 2006, p. 502-512, Vol. 26, No. 2
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.2.502-512.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Hzf, a p53-Responsive Gene, Regulates Maintenance of the G2 Phase Checkpoint Induced by DNA Damage{dagger}

Masataka Sugimoto,1,2 Adam Gromley,2 and Charles J. Sherr1,2*

Howard Hughes Medical Institute,1 Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, Tennessee 381052

Received 9 August 2005/ Returned for modification 27 September 2005/ Accepted 18 October 2005

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 G2 phase arrest following ionizing radiation (IR), thereby sensitizing cells to DNA damage. Canonical p53-responsive gene products such as p21Cip1 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 p21Cip1, an inhibitor of cyclin-dependent kinases whose expression contributes to maintaining the duration of the G2 checkpoint in cells that have sustained DNA damage. Thus, two p53-inducible gene products, Hzf and p21Cip1, act concomitantly to enforce the G2 checkpoint.

* Corresponding author. Mailing address: Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105. Phone: (901) 495-3505. Fax: (901) 495-2381. E-mail: charles.sherr{at}stjude.org.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2006, p. 502-512, Vol. 26, No. 2
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.2.502-512.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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