Transcriptional Regulation by Wild-Type and Cancer-Related Mutant Forms of p53

Abstract

TP53 missense mutations produce a mutant p53 protein that cannot activate the p53 tumor suppressive transcriptional response, which is the primary selective pressure for TP53 mutation. Specific codons of TP53, termed hotspot mutants, are mutated at elevated frequency. Hotspot forms of mutant p53 possess oncogenic properties in addition to being deficient in tumor suppression. Such p53 mutants accumulate to high levels in the cells they inhabit, causing transcriptional alterations that produce pro-oncogenic activities, such as increased pro-growth signaling, invasiveness, and metastases. These forms of mutant p53 very likely use features of wild-type p53, such as interactions with the transcriptional machinery, to produce oncogenic effects. In this review, we discuss commonalities between wild-type and mutant p53 proteins with an emphasis on transcriptional processes.

Figure 1.

Transcriptional model for wild-type and mutant p53. (A) Transcriptional model for wild-type p53. Wild-type p53 is modified at specific amino acids in response to cellular stress signals, such as DNA damage, and accumulates at the protein level in part because of decreased degradation by MDM2. p53 has an intact DNA-binding domain and thus recognizes its cognate p53 response element (RE), which it preferentially binds. p53 then recruits other transcriptional regulatory components, such as transcription factors (TFs) and histone acetyltransferases (HATs) such as p300. HATs acetylate (+Ac) p53 as well as chromatin, promoting additional steps toward transcription, such as the stable recruitment of chromatin remodeling complexes (CRCs) such as SWI/SNF. CRCs recognize histone tails that are primed with histone modifications at specific residues, which promotes ATP-dependent histone displacement or eviction by the CRC. RNA polymerase II and other general TFs bind to the open promoter, forming the pre-initiation complex, followed by steps leading to transcriptional elongation. For a more detailed explanation, see the text. (B) Transcriptional model for mutant p53 (Mut p53). Mutant p53 is accumulated at the protein level because of impairment of MDM2 induction and deregulated posttranslational modifications, among other mechanisms. The mutant p53 DNA-binding domain does not recognize the p53 RE, so mutant p53 interaction with chromatin is primarily through protein–protein interactions with other transcriptional regulators such as transcription factors. Because mutant p53 is not restricted through specific binding to the p53 RE, mutant p53 is associated across the genome in a promiscuous manner. At genes that are primed for transcription, such as by being bound by a pioneering transcription factor as well as a chromatin remodeling complex (see Pfister et al. 2015), mutant p53 may promote transcription. Mutant p53 is recruited through protein–protein interactions (that may be conserved in wild-type p53) to such promoters, followed by mutant p53-dependent recruitment of additional transcriptional regulators such as TFs and HATs. Transcription then proceeds in a manner generally similar to that of wild-type p53. Therefore, a key distinction is that wild-type p53 is capable of independently facilitating CRC recruitment and transcriptional activation, while mutant p53 is dependent on the presence of specific promoter factors such as SWI/SNF. Most importantly, wild-type p53 is restricted to specific genomic sites (at p53 responsive genes) by virtue of its DNA-binding domain, whereas mutant p53 is not restricted to specific genomic sequences.