Molecules in focus
p73

https://doi.org/10.1016/S1357-2725(01)00073-5Get rights and content

Abstract

The discovery of p73 as a family member of p53 has instigated a number of studies in search of its function, regulation, and involvement in tumorigenesis. p73 has been identified as a transcription factor that can regulate p53-dependent transcriptional targets. Similarly to p53, p73 can induce apoptosis in response to various stimuli, including certain types of DNA damage. This evidence suggests that p73 may act as a tumor suppressor with overlapping functions of p53. While mutations of p73 appear rare in human tumors, some leukemias have shown silencing of the gene by hypermethylation. Thus, introduction of p73 into tumor cells possessing inactive p53 may provide a valuable therapeutic approach.

Introduction

Commonly referred to as the guardian of the genome, p53 is distinguished as the most frequently mutated gene in human cancer being mutated or lost in 50% of tumors [1]. The importance of the p53 tumor suppressor gene stems from its ability to induce both cell cycle arrest and apoptosis in response to a wide range of genotoxic and cellular stresses. p53 plays a critical role as a transcription factor by transcribing genes, such as p21, Bax, and preventing damaged DNA replication and division of genetically modified cells [1].

Given the importance of p53, it is not surprising that a significant effort has been put forth to identify p53 homologues. While searching for response genes to immune system regulatory events, Kaghad et al. in 1997 serendipitously discovered p73 [2]. Due to its considerable homology to p53, initial speculation was that p73 may function similarly to p53. In addition, the importance of p73 as another tumor suppressor was suggested by its location at chromosome 1p36, a region frequently deleted in neuroblastoma and other tumors [2]. However, mutations in p73 from tumors have been rarely observed.

Section snippets

Structure

The p53 family contains, in addition to p73, another recently identified gene, p63. p73 and p63 are more closely related to each other than to p53; however, all these molecules possess considerable homology to one another (Fig. 1A). Alternative splicing primarily at the three end of the human p73 gene generates at least six variants, α, β, δ, γ, ε, ζ [3] (Fig. 1B). Like p53, p73 and p63 contain a transactivation domain (TAD), a DNA binding domain (DBD), and an oligomerization domain (OD). The

Synthesis and degradation

p73 transcripts have been identified in human thymus, prostate, heart, liver, skeletal muscle, and pancreas by northern blot analysis [1]. Partial characterization of the p73 promoter has revealed putative SP1, AP2, Erg-1, Erg-2, Erg-3 sites and a TATA-like box. Additional putative SP1 sites, multiple E2F and AP-2 sites, and a c-Myb site have been identified further upstream from exon I [3]. With the exception of regulation by E2Fs, regulation of p73 by these other transcription factors remains

Biological function

Homologous DBDs and ODs between p53 and p73 indicate that p73 is a transcription factor which may target p53-dependent genes. By expressing recombinant constructs containing the OD, p73 exists primarily as a tetramer [9]. Induction of p73 by transfection has been demonstrated to induce the transcription of endogenous p21, a p53-dependent gene [8]. Likewise, several other studies report p73 induction of other p53-mediated genes such as Bax, MDM2, GADD45, and cyclin G [3]. However, to date

Medical implications

p73's classification as a tumor suppressor remains controversial, and given that p73 is rarely mutated in human tumors, it is highly unlikely that p73 acts as a tumor suppressor like p53. Indeed, p73 expression is higher in tumors including lung, breast, bladder, neuroblastoma, and hepatocellular carcinoma than the tissue of origin. However, most of these studies were carried out by RT-PCR, and p73 protein levels were not examined [3]. Other studies have observed abnormal splicing variants of

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