Hzf Determines cell survival upon genotoxic stress by modulating p53 transactivation.
A critical unresolved issue about the genotoxic stress response is how the resulting activation of the p53 tumor suppressor can lead either to cell-cycle arrest and DNA repair or to apoptosis. We show here that hematopoietic zinc finger (Hzf), a zinc-finger-containing p53 target gene, modulates p53 transactivation functions in an autoregulatory feedback loop. Hzf is induced by p53 and binds to its DNA-binding domain, resulting in preferential transactivation of proarrest p53 target genes over its proapoptotic target genes. Thus, p53 activation results in cell-cycle arrest in Hzf wild-type MEFs, while in Hzf(-/-) MEFs, apoptosis is induced. Exposure of Hzf null mice to ionizing radiation resulted in enhanced apoptosis in several organs, as compared to in wild-type mice. These findings provide novel insights into the regulation of p53 transactivation function and suggest that Hzf functions as a key player in regulating cell fate decisions in response to genotoxic stress.
Das
Sanjeev
S
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Raj
Lakshmi
L
Zhao
Bo
B
Kimura
Yuki
Y
Bernstein
Alan
A
Aaronson
Stuart A
SA
Lee
Sam W
SW
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage; D025461:Feedback, Physiological; D005260:Female; D005720:Gamma Rays; D005982:Glutathione Transferase / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008954:Models, Biological; D012516:Osteosarcoma / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D014916:Whole-Body Irradiation
D011506:Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; C404217:Zfp385 protein, mouse; D005982:Glutathione Transferase
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