Hzf Determines Cell Survival upon Genotoxic Stress by Modulating p53 Transactivation

Abstract

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.

The dark side of a tumor suppressor: anti-apoptotic p53

“…Interestingly, this effect was accompanied by increased polyubiquitination and turnover of p21, an event that was only explained very recently. 137 Here the authors confirmed that also human Hzf is under the control of p53 and modulates p53 transactivation functions in an autoregulatory feedback loop. This pathway was uncovered by the observation that in the presence of Hzf p53 predominantly binds to promoters of pro-arrest targets such as p21 and 14-3-3d, whereas this association significantly decreased in Hzf-deficient cells with a concomitant enhancement of p53 bound to promoters of pro-apoptotic genes.…”

“…137 Interestingly, the authors also found that the level of Hzf protein correlated inversely with the extent of a genotoxic stress signal as Hzf undergoes extensive ubiquitination and proteasomal degradation following prolonged stress exposure resulting in induction of pro-apoptotic genes. Together, these data provide an attractive explanation for the observation that extended damage triggers a switch from a growth-inhibitory transcriptional program to a pro-apoptotic one.…”

UV‐induced interaction between p38 MAPK and p53 serves as a molecular switch in determining cell fate

“…The damaged cell is confronted with a choice: repair and live, or die. This process is basically decided by p53, largely through different post-translational modifications and specific induction of its target genes [1,3,18]. Several studies have thrown light on the notion that different doses or wavelengths of UV radiation may bring about different cell fates [14,[19][20][21]], yet a gap in our understanding on how different UV doses lead to different modifications of p53 still exists.…”

Mechanisms of regulatory diversity within the p53 transcriptional network

“…In a recent report, a novel p53 cofactor, named hematopoietic zinc-finger (HZF), has been characterized as a key determinant of gene selectivity within the p53 network (Das et al, 2007). The Hzf gene itself is transcriptionally activated by p53 and the protein product directly associates with the p53 DBD.…”