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Abstract
p53 is a sequence‐specific transcription factor, and proper regulation of p53 transcriptional activity is critical for orchestrating different tumor‐suppressive mechanisms. p32 is a multifunctional protein which interacts with a large number of viral proteins and transcription factors. Here, we investigate the effect of p32 on p53 transactivation and identify a novel mechanism by which p32 alters the functional characteristics of p53. Specifically, p32 attenuates p53‐dependent transcription through impairment of p53 binding to its response elements on target genes. Upon p32 expression, p53 levels bound at target genes are decreased, and p53 target genes are inactivated, strongly indicating that p32 restricts p53 occupancy and function at target genes. The primary mechanism contributing to the observed action of p32 is the ability of p32 to interact with the p53 tetramerization domain and to block p53 tetramerization, which in turn enhances nuclear export and degradation of p53, leading to defective p53 transactivation. Collectively, these data establish p32 as a negative regulator of p53 function and suggest the therapeutic potential of targeting p32 for cancer treatment.
Highlights
P32, known as gC1qR/C1QBP/HABP1, was first identified as a factor that is associated with splicing factors and is required for 50 splice site cleavage and lariat formation during pre-mRNA splicing in HeLa cells (Krainer et al, 1990)
Another argument in favor of p32 to act as a master p53 repressor comes from our cellular experiments showing that the expression of p32 in p53-transfected H1299 cells leads to a reduced transcription of p53 target genes
In an effort to decipher the molecular basis underlying p32 transrepressive activity, we found that p32 directly interacts with the C-terminal tetramerization domain of p53 and successfully competes for p53 residues that mediate its tetramerization. p53 binds its DNA response elements most efficiently as a tetramer, and tetrameric p53 is most effective for transactivation of target genes
Summary
P32, known as gC1qR/C1QBP/HABP1, was first identified as a factor that is associated with splicing factors and is required for 50 splice site cleavage and lariat formation during pre-mRNA splicing in HeLa cells (Krainer et al, 1990). P32 was shown to have the ability to interact with several viral proteins including core protein V of adenovirus, ORF P of herpes simplex virus, EBNA-1 of Epstein–Barr virus, and HIV-1 Tat and Rev (Bruni and Roizman, 1996; Desai et al, 1991; Fridell et al, 1995; Luo et al, 1994; Matthews and Russell, 1998; Tange et al, 1996; Wang et al, 1997; Yu et al, 1995; Yu et al, 1995) These results suggest its possible importance in the regulation of replication and generation of viral particles. Cancer cells developed several strategies to escape from p53-mediated stress response, one of which is the inhibition of tetramer formation In this regard, several mutations in the tetramerization domain of p53 have been reported to compromise p53 tetramer formation and thereby inhibit DNA binding and transactivation activity (Chene, 2001). Previous reports showed that some of the p53-interacting proteins decrease the DNA binding potential of p53 by blocking the formation of the tetramers, which provides mechanistic insights into how their presence can convert p53 target genes from an active state to a latent inactive state (van Dieck et al, 2009; Foo et al, 2007; Lin et al, 2004; Lui et al, 2015)
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