Oncogenic Mutant p53 Gain of Function Nourishes the Vicious Cycle of Tumor Development and Cancer Stem-Cell Formation

Shetzer, Yoav; Molchadsky, Alina; Rotter, Varda

doi:10.1101/cshperspect.a026203

Cited by 42 publications

(39 citation statements)

References 198 publications

(207 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…17,20,71,95 However, different TP53 mutants are believed to acquire GOF, with varied effect size according to the mutation site and specific amino acid change. 96 Although wild-type TP53 acts as a tumor suppressor by activating downstream target genes, GOF are thought to mostly result from the binding of mutant TP53 to different proteins, including transcription factors. 89,97 Among the cellular impacts of mutant TP53 GOF in AML are genomic destabilization, loss of cell-cycle control, enhanced proliferation of tumor cells, and chemoresistance.…”

Section: Aml-related Tp53 Mutationsmentioning

confidence: 99%

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

Barbosa

Adams

et al. 2019

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancer. The central role of the TP53 protein in several fundamental processes such as cancer, aging, senescence, and DNA repair has ensured enormous attention. However, the role of TP53 in acute myeloid leukemia (AML) is enigmatic. Unlike many other human cancers, a vast majority of AMLs display no genomic TP53 alterations. There is now growing appreciation of the fact that the unaltered TP53 status of tumor cells can be exploited therapeutically. As most AMLs have an intact TP53 gene, its physiological tumor‐suppressive roles could be harnessed. Therefore, the use of pharmacological activators of the TP53 pathway may provide clinical benefit in AML. Conversely, even though the frequency of TP53 mutations in AML is substantially lower than in other human cancers, TP53 mutations are associated with chemoresistance and high risk of relapse. In patients with TP53 mutations, these alterations may lead to novel, selective vulnerabilities, creating opportunities for therapeutic targeting of TP53 mutant AML. The mutational status of TP53 therefore poses challenges and opportunities in terms of advancing effective treatment strategies in AML. An increasing armamentarium of small‐molecule activators of the TP53 pathway, and a growing understanding of molecular pathways triggered by mutant TP53 have accelerated efforts aimed at targeting TP53 function in AML. In combination with standard AML chemotherapy or emerging targeted therapies, pharmacological targeting of the TP53 pathway may provide therapeutic benefit in AML.

show abstract

Section: Aml-related Tp53 Mutationsmentioning

confidence: 99%

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

Barbosa

Adams

et al. 2019

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

show abstract

“…These observations may hold some valuable insights into the molecular mechanisms contributing to tumorigenesis in these cancers. For example, evidence from both in vitro and in vivo studies has shown the missense mutations in p53 both eliminate the normal functions of the protein, but also have additional gain-of-function (GOF) properties that contribute to tumorigenesis (Lang et al 2004;Olive et al 2004;Oren and Rotter 2010;Shetzer et al 2016). In tumors that show high proportions of missense mutations in p53, this GOF might be an important contributing factor in tumor development.…”

Section: Tumor Specificity In P53-pathway Inactivation Tumors With Simentioning

confidence: 99%

Attenuating the p53 Pathway in Human Cancers: Many Means to the Same End

Wasylishen

Lozano

2016

Cold Spring Harb Perspect Med

111

View full text Add to dashboard Cite

The p53 pathway is perturbed in the majority of human cancers. Although this most frequently occurs through the direct mutation or deletion of p53 itself, there are a number of other alterations that can attenuate the pathway and contribute to tumorigenesis. For example, amplification of important negative regulators, MDM2 and MDM4, occurs in a number of cancers. In this work, we will review both the normal regulation of the p53 pathway and the different mechanisms of pathway inhibition in cancer, discuss these alterations in the context of the global genomic analyses that have been conducted across tumor types, and highlight the translational implications for cancer diagnosis and treatment.

show abstract

“…42 Moreover, p53 GOF mutants attenuate antioxidant enzymes, thereby contributing to AML-related ROS accumulation while promoting cell survival and abrogating the DDR. 41,54 Mutp53 GOF promotes cell proliferation and chemoresistance…”

Section: 263452mentioning

confidence: 99%

“…Nevertheless, different p53 mutants acquire GOF, which vary in their effect and magnitude as a function of mutation site and nucleotide substitution type. 41 Hence, mutp53 represents a heterogeneous protein population with divergent potential to serve as "druggable" targets ( Figure 2). 11 The major cellular impacts of mutp53 GOF in AML include genomic destabilization and disruption of the DNA damage response (DDR), loss of cell-cycle control, enhanced tumor cell proliferation, and chemoresistance.…”

mentioning

confidence: 99%

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

Prokocimer

Molchadsky

Rotter

2017

Blood

Self Cite

138

119

View full text Add to dashboard Cite

The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis. While in human solid tumors TP53 is mutated in more than half of cases, TP53 mutations occur in less than one tenth of de novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to nonmutational p53 abnormalities appears to be rather frequent in various AML entities, bearing, presumably, a greater impact than is currently appreciated. Hereby, we advocate assessment of adult AML with respect to coexisting p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function but also on the mechanisms underlying nonmutational wtp53 inactivation, which might be of therapeutic relevance. Patient-specific TP53 genotyping with functional evaluation of p53 protein may contribute significantly to the precise assessment of p53 status in AML, thus leading to the tailoring of a rationalized and precision p53-based therapy. The resolution of the mechanisms underlying p53 dysfunction will better address the p53-targeted therapies that are currently considered for AML. Additionally, a suggested novel algorithm for p53-based diagnostic workup in AML is presented, aiming at facilitating the p53-based therapeutic choices. (Blood. 2017; 130(6):699-712)

show abstract

Oncogenic Mutant p53 Gain of Function Nourishes the Vicious Cycle of Tumor Development and Cancer Stem-Cell Formation

Cited by 42 publications

References 198 publications

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

Attenuating the p53 Pathway in Human Cancers: Many Means to the Same End

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

Contact Info

Product

Resources

About