Alterations of p63 and p73 in Human Cancers

Abstract

Summary p53 and its related genes, p63 and p73 constitute the p53 gene family. While p53 is the most frequently mutated gene in human tumors, p63 and p73 are rarely mutated or deleted in cancers. Many studies have reported p63/p73 overexpression in human cancers while others showed that a loss of p63/p73 is associated with tumor progression and metastasis. Thus, whether p63 or p73 is a tumor suppressor gene or an oncogene has been a matter of debate. This controversy has been attributed to the existence of multiple splicing isoforms with distinct functions; the full-length TA isoform of p63 has structural and functional similarity to wild-type p53, whereas the ΔNp63 acts primarily in dominant-negative fashion against all family members of p53. Differential activities of TA and ΔN isoforms have been shown in vivo by creating isoform-specific gene knockout mice. All p53, p63, p73 proteins bind to and activate target genes with p53-response elements; p63 also binds to distinct p63-response elements and regulate expression of specific target genes involved in skin, limb, and craniofacial development. Interestingly, several studies have shown that both p63 and p73 are involved in cellular response to cancer therapy and others have indicated that both of these molecules are required for p53-induced apoptosis, suggesting functional interplay among p53 family proteins. Consistent with these findings, aberrant splicing that result in ΔNp63 or ΔNp73 overexpression are frequently found in human cancers, and is associated with poor clinical outcomes of patients in the latter. Thus immunohistochemical staining of tumor specimen with ΔNp73-specific antibody might have diagnostic values in cancer clinics.

ΔNp63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer

“…Therefore, in contrast to the several mechanisms used to reactivate mutant p53 proteins in human tumors that have unfortunately failed so far in clinical trials (Muller and Vousden, 2014), the inhibition of ΔNp63, which is rarely mutated in human cancers (Inoue and Fry, 2014), could result in a more efficacious strategy. Given the difficulties in directly targeting a transcription factor compared to “druggable” factors such as kinases (Yeh et al, 2013), we decided to screen more than 850 pharmacologically active compounds in an effort to repurpose existing drugs for their ability to mimic ΔNp63 deletion and downregulation of its downstream transcriptional target, DGCR8 .…”

ΔNp63α Acts as a Lineage-Survival Oncogene in Squamous Cell Carcinoma

“…Particularly because the majority of SCCs overexpress ΔNp63α, often as a result of amplification of the TP63 genomic region [2,3]. In agreement, numerous in vitro studies highlight ΔNp63α as a potential oncogene, due to its ability to bypass oncogene-induced senescence, inhibit apoptosis or induce angiogenesis.…”

“…In agreement, numerous in vitro studies highlight ΔNp63α as a potential oncogene, due to its ability to bypass oncogene-induced senescence, inhibit apoptosis or induce angiogenesis. On the other hand, observations in patients and genetic mouse models with single-allelic loss of p63 reveal an inverse correlation between ΔNp63α levels and tumor invasiveness and metastasis [2,3]. In addition, tumor ΔNp63α levels were shown to correlate both with better or worse therapeutic responses, adding additional complexity on the diverse regulatory actions of ΔNp63α [3].…”

Aberrant splicing of the DMP1‐ARF‐MDM2‐p53 pathway in cancer

“…The alternative splicing (AS), differential selection of splice sites present within a pre‐mRNA, leads to a production of multiple mRNAs from a single gene with divergent functions. A frequent outcome of AS is the production of proteins with a similar, dominant‐negative or even opposing functions as represented by overexpression of oncogenic ΔN isoforms from the p63 and p73 loci, and many genes in the proapoptotic pathway also give rise to antiapoptotic isoforms by AS . This mechanism gives opportunities for cancer cells to produce proteins that accelerate cell growth, inhibit apoptosis and promote metastasis.…”

“…Several splicing factors, RNA‐binding proteins regulating AS have been identified as proto‐oncogenes and are overexpressed in human cancers . Multiple cancer‐associated genes such as Cyclin D1 , PKM , Bcl‐x , CD44 , hnRNP , p63 and p73 are alternatively spliced in tumors compared to adjacent normal . The activities of these tumor‐associated splice isoforms vary from regulation of novel biological processes to dominant‐negative regulation of the isoforms expressed in normal tissues …”