TP53 Mutants in the Tower of Babel of Cancer Progression

Abstract

Loss-of-function, partial-function, alteredfunction, dominant-negative, temperature sensitive, interfering, contact, structural, unfolded, misfolded, dimeric, monomeric, non-cooperative, unstable, supertrans, superstable, intragenic suppressor. TP53 mutants are many, more than 2,000 in fact, and they can be very diverse. Sporadic; germline; gain-of-function (GoF); oncogenic; rebel-angel; yin and yang; prion-like; metastasis-inducer; mediator of chemo-resistance; modifier of stemness. TP53 mutants can impact important cancer clinical variables, in multiple, often subtle ways, as revealed by cell-based assays as well as animal models. Here, we review studies investigating TP53 mutants for their effect on sequencespecific transactivation function, and especially recent findings on how TP53 mutants can exhibit GoF properties. We also review reports on TP53 mutants' impact on cancer cell transcriptomes and studies with Li-Fraumeni patients trying to classify and predict phenotypes in relation to experimentally determined transcription fingerprints. Finally, we provide an example of the complexity of correlating TP53 mutant functionality to clinical variables in sporadic cancer patients. Conflicting results and limitations of experimental approaches notwithstanding, the study of TP53 mutants has provided a rich body of knowledge, mostly available in the public domain and accessible through databases, which is beginning to impact cancer intervention strategies.

Mutant p53 (p53-R248Q) functions as an oncogene in promoting endometrial cancer by up-regulating REGγ

“…Mutations at these residues can interfere with the tumor suppression function of p53 through either dominant-negative or GOF effects, both of which are related to poor cancer prognosis [41,42]. P53 GOF mutations have not yet been extensively studied in EC, but the R175H, R248Q and R273H mutants have been examined.…”

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

“…A dominant-negative effect also likely occurs via high-level oligomeric states in which aggregated mutant p53 sequesters WT p53 into mixed oligomers (Ano Bom et al 2012). Several oncogenic functions of mutant p53 have been characterized (Muller and Vousden 2013;Bisio et al 2014), but these functions are beyond the scope of this review.…”

Clinical Outcomes of TP53 Mutations in Cancers

“…These mutations can be broadly categorized on the basis of the type of molecular disruption and the biological consequences on the wild-type (WT) p53 protein. TP53 mutations may lead to complete loss of tumor-suppressor properties (loss of function), enable mutated p53 to form a heterodimer with the remaining WT protein and block its activity (dominantnegative), or confer a conformational change on the protein that allows it to interact differently with its downstream effector proteins or bind entirely new DNA target sequences gain of function (GOF) (Oren and Rotter 2010;Bisio et al 2014). A more detailed picture of the impact of TP53 somatic mutations on the outcome of cancer patients has started to emerge through the systematic classification of missense TP53 mutations based on DNA binding and transcriptional and oncogenic properties of mutant p53.…”