The p73 gene, a member of the p53 family, is controlled by two alternate promoters. When the upstream P1 promoter is used for p73 expression, several TAp73 isoforms are produced. When the P2 promoter in intron 3 is used for p73 expression, several ANp73 isoforms are produced. Since the AN isoforms lack the N-terminal activation domain conserved in p53, they are assumed to be inactive in transcription. Interestingly, we found that the thirteen unique residues together with the N-terminal PXXP motif in ANp73 constitute a novel activation domain. Furthermore, we found that TAp73 and ANp73 regulate both common and distinct groups of target genes. Due to its sequence similarity with p53, p73 has many p53-like activities. These include the ability to induce cell cycle arrest, apoptosis, differentiation, and senescence. Thus, p73 is a tumor suppressor. Consistent with this, p73 status is linked to increased survival rates and loss of p73 expression is linked to increased metastasis potentials in many types of human cancer. Likewise, mice heterozygous of p73 are prone to increased tumor burdens and metastasis rates, which are compounded in mice harboring heterozygous alleles of p53 andlor p63. However, p73 is not a classic tumor suppressor since mutant mice are also prone to developmental defects, chronic infection and inflammation. Previously, we and others showed that p73 expression is activated by stress signals, such as DNA damage. These stress signals are known to stabilize and activate p53 primarily via post-translational modifications. In contrast, transcriptional regulation of the p73 gene is found to be critical for activation of p73 upon DNA damage. In an effort to characterize p73 functional domains and transcriptional activity, we identified histone deacetylases (HDACs) as a co-repressor of p73. We also identified several novel p73 targets, including Dccl, a basic helix-loop-helix transcription factor, and RNPC1, a RNA-binding protein. Interestingly, we found that HDACs, Dec 1 and RNPC I are capable of regulating p73 expression. Thus, we hypothesize that in response to stress signals, HDACs, RNPC1 and Dccl serve as an effector and a modulator of the p73 pathway. To test this, the following three specific aims are proposed to: (1) determine whether various p73 isoforms are differentially regulated by HDACs;(2) determine whether various p73 isoforms are differentially regulated by Dccl, a basic helix-loop-helix transcription factor and a target of p73;and (3) determine whether various p73 isoforms are differentially regulated by RNPCI, a RNAbinding protein and a target of p73.
Mechanism of P73-Dependent Tumor Suppression Public Health Relevance Statement P73 is a tumor suppressor. Consistent with this, p73 status is linked to increased survival rates and loss of p73 expression is linked to increased metastasis potentials in many types of human cancer. Likewise, mice heterozygous of p73 are prone to increased tumor burdens and metastasis rates, which are compounded in mice harboring heterozygous alleles of p53 and/or p63. The proposed study is to analyze how p73 expression is regulated by HDACs, RNPC1 and Dec1. Listed below are some of the rationales why the proposed study is relevant to human health. (1) HDAC inhibitors are emerging as promising cancer therapeutics. It has been hypothesized that the p53 pathway activated by HDAC inhibitors is necessary for tumor suppression in cells with wild-type p53. However, it remains uncertain whether activation of the p53 pathway is sufficient and what is responsible for tumor suppression in cells with mutant p53. Since p73 is rarely mutated in human tumors, the proposed study to examine the crosstalk between the p73 pathway and HDACs becomes significant. (2) p73 is expressed as two major isoforms, TAp73 and DNp73, which are differentially expressed in various cell types and tissues. In addition, these p73 isoforms have distinct transcriptional and biological activities. Thus, how these p73 isoforms are differentially regulated by HDACs, RNPC1 and Dec1 may elucidate the mechanism by which the expression patterns and biological activities of p73 are regulated. (3) DNp73 is found to be amplified and/or over-expressed in many tumors and correlated with tumor progression and poor prognosis. Thus, the regulation of DNp73 expression by HDACs, RNPC1 and Dec1 can be explored as a potential therapeutic strategy to manage tumors with amplified and/or over-expressed DNp73.
Showing the most recent 10 out of 72 publications
