It is widely accepted that the p53 tumor suppressor restricts abnormal or DNA damage-exposed cells before damage to DNA is converted to inherited mutation by induction of growth arrest or by triggering apoptosis. This process depends mainly on the expression of genes that regulate cell-cycle arrest or apoptosis. A critical unresolved issue about the DNA damage response is how the resulting up- regulation of the p53 tumor suppressor can lead either to cell cycle arrest/senescence andDNA repair, or to apoptosis. Over the course of this grant period, we have identified the Hematopoietic zinc finger protein (Hzf) gene as a novel target gene of p53 and p53-dependent DNA damage. We found that Hzf modulates p53 transactivation functions by positively regulating genes involved in cell cycle arrest and negatively regulating those with pro-apoptotic functions. Our preliminary results also show that Hzf is induced by p53 and directly binds to the DNA binding domain of p53, resulting in preferential transactivation of its cell cycle arrest mediating target genes, p21 and 14-3-3g,but inhibiting transactivation of pro-apoptotic p53 target genes such as Bax, Noxa, Puma, and Perp. Thus, p53 activation in response to DNA damage results in cell cycle arrest in Hzf wt-MEFs, while in Hzf -/- MEFs apoptosis is induced. We, therefore, hypothesize that Hzf is a critical modulator of p53-mediated transcription in DNA damage/stress response and functions as a key player in controlling a cellular regulatory switch that dictates the cellular decision toward cell cycle arrest. In this renewal application, we will continue to address whether or not Hzf-assisted transcription controls p53-cell fate decisions determining arrest and apoptosis, and will also investigate whether Hzf regulates the tumor suppressor function of p53 in vivo using Hzf-null mice. Since the consequence of the absence or degradation of Hzf protein is irreversible cell death, defects in the Hzf activation pathway may confer resistance to the cytotoxic effect of chemo- and radio-therapeutic agents. Thus, this novel layer of the Hzf pathway may provide important implications for our understanding of DNA damage checkpoint signaling, as well as novel mechanisms of anti-cancer resistance in cancer patients. Finally, results from the proposed work may lead to new, mechanism-based strategies for increasing the efficacy of chemo- and radiation- therapies.
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