The role of mutant p53 in human cancer

  title={The role of mutant p53 in human cancer},
  author={Amanda Goh and Cynthia R. Coffill and David P Lane},
  journal={The Journal of Pathology},
Mutations in the TP53 (p53) gene are present in a large fraction of human tumours, which frequently express mutant p53 proteins at high but heterogeneous levels. The clinical significance of this protein accumulation remains clouded. Mouse models bearing knock‐in mutations of p53 have established that the mutant p53 proteins can drive tumour formation, invasion and metastasis through dominant negative inhibition of wild‐type p53 as well as through gain of function or ‘neomorphic’ activities… 
Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others
This Review proposes a categorization of the major classes of p53 mutants based on their functionality in tumour suppression and response to therapy, and suggests that the mutations across TP53 form a 'rainbow of mutants', with varying degrees of functionality and different pathobiological consequences.
Targeting mutant p53 in human tumors.
  • B. LehmannJ. Pietenpol
  • Biology, Medicine
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2012
Results of the trial show that the APR-246 (PRIMA-1) molecule is safe at therapeutic plasma levels and can induce p53-dependent biologic effects, and represent a major step forward in targeting the most frequently altered pathway in cancer.
The p53 Tumor Suppressor Pathway in Tumorigenesis and Therapy
In several genetic models of murine tumor development, loss of p53 facilitates oncogenesis, and, in some cases, may even be required for the disease phenotype, and well-characterized oncoproteins that have been shown to be the transforming agents of several DNA tumor viruses function by binding and inactivating known bind and target p53 degradation.
Wild-type and mutant p53 mediate cisplatin resistance through interaction and inhibition of active caspase-9
It is demonstrated that p53, when present at high levels in the cytoplasm, has an inhibitory effect on caspase-9, and the inhibition of caspASE-9 as a potential mechanism in evading apoptosis in tumors with high-level p53 expression that is cy toplasmically localized.
Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice
It is shown for the first time that similarly elevated levels of Mutant p53 can be detected in apparently normal cells in a mutant p53 knock-in mouse model and the small intestine of these p53 mutant mice is an experimental system in which the molecular pathways leading to p53 accumulation are dissected.
New therapeutic strategies to treat human cancers expressing mutant p53 proteins
Mouse models show that the genetic reconstitution of the wild type p53 tumor suppression functions rescues tumor growth, which strongly supports the notion that either restoring wt-p53 activity or inhibiting mutant p53 oncogenic activity could provide an efficient strategy to treat human cancers.
Mutant p53 gain of function is interwoven into the hallmarks of cancer
This commentary links mutant p53 activities to the hallmarks of cancer, describing its involvement in resistance to apoptosis, genomic instability, aberrant cell cycle, invasion and metastasis, tumour microenvironment, and inflammation.
Regulation of the p53 response and its relationship to cancer.
  • D. Meek
  • Biology
    The Biochemical journal
  • 2015
P53 has been studied intensively as a major tumour suppressor that detects oncogenic events in cancer cells and eliminates them through senescence or apoptosis, and its regulatory contributions and ability to integrate signals from cellular events towards providing most appropriate response to stress conditions are examined.
Genomic Instability: The Pivotal Role of Mutant P53 in Human Cancers
Accumulating evidences suggest that mutant p53 proteins drastically perturb the residual genome-stabilizing mechanisms during cancer progression, thereby increasing genomic instability of Mutant p53 carrying human cancers.
Targeting tumor suppressor p53 for cancer therapy: strategies, challenges and opportunities.
The therapeutic potential of p53 is discussed, with particular focus on the therapeutic strategies to rescue p53 inactivation in human cancers, and the challenges of p 53-targeted therapy and new opportunities for the future are discussed.


Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression
It is found that depletion of mutant p53 reduces cell proliferation, in vitro and in vivo tumorigenicity, and resistance to anticancer drugs.
p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM
P53 gain-of-function mutants promote tumorigenesis by a novel mechanism involving active disruption of critical DNA damage-response pathways, as indicated by several lines of evidence.
Mutant p53 gain-of-function in cancer.
The biological manifestations of mutant p53 gain-of-function, the underlying molecular mechanisms, and their possible clinical implications are addressed.
The R246S hot-spot p53 mutant exerts dominant-negative effects in embryonic stem cells in vitro and in vivo
It is demonstrated here that R246S mutant p53 exhibits DN effects with respect to target gene expression, cell survival and cell cycle arrest both in cells that are in the undifferentiated state and upon differentiation.
p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding
It is proposed that tumour lines which express high levels of transcriptionally inactive mutant p53 are unable to induce the expression of the Mdm2 protein which would normally provide a feedback mechanism down-regulating p53 protein levels in the absence of DNA damage signals.
p73 can suppress the proliferation of cells that express mutant p53
Wild-type p73β, in the presence of mutant p53, retains the ability to transactivate p21 and suppresses cell growth through induction of both cell cycle arrest and apoptosis, and it is found that these proteins cooperate to additively transactivatep21 and suppress cell proliferation.
Physical and Functional Interaction between p53 Mutants and Different Isoforms of p73*
A network involving mutant p53 and the various spliced isoforms of p73 that may confer upon tumor cells a selective survival advantage is defined, which is defined as a network involving p53His175 and p53Gly281 and can associate with p73 not only physically but also functionally.
The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss.
The regulation of mutant p53 stability by Mdm2, an E3 ubiquitin ligase that targets p53 for degradation, and p16INK4a, a member of the Rb tumor suppressor pathway are examined to indicate that drugs aimed at activating wild-type p53 will also stabilize Mutant p53 with dire consequences.
Mutant p53 protein expression interferes with p53-independent apoptotic pathways
Observations suggest that while loss of wild type p53 function clearly reduces the rate of apoptosis, p53 mutations may result in a gain of function which significantly interferes with chemotherapy induced apoptosis.