Das S, Raj L, Zhao B, Kimura Y, Bernstein A, Aaronson SA, Lee SW

Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

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.

Mesh Terms:
Animals, Apoptosis, Cell Culture Techniques, Cell Line, Tumor, Cell Survival, DNA Damage, Feedback, Physiological, Female, Gamma Rays, Glutathione Transferase, HCT116 Cells, Humans, Immunohistochemistry, Male, Mice, Models, Biological, Osteosarcoma, Prostatic Neoplasms, Proteins, RNA, Small Interfering, Recombinant Proteins, Transcriptional Activation, Tumor Suppressor Protein p53, Two-Hybrid System Techniques, Whole-Body Irradiation

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