Abstract
The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 negative regulators, such as murine double minute 2 (MDM2) or murine double minute 4 (MDM4), epigenetic deregulation, or even alterations in TP53 mRNA splicing. In this work, we will review the different mechanisms of p53 pathway inhibition in cancer with special focus on multiple myeloma (MM), the second most common hematological malignancy, with low incidence of p53 mutations/deletions but growing evidence of indirect p53 pathway deregulation. Translational implications for MM and cancer prognosis and treatment are also reviewed.
Highlights
Since its discovery in 1979, the tumor suppressor protein p53 has been extensively studied. p53 is a transcription factor activated in response to several forms of cellular stress including DNA damage, hypoxia, viral infection, heat shock, and mitogenic or oncogenic stresses among others [1,2,3]. p53 pathway activation is mediated by the protein stabilization, via the disruption of a p53/murine double minute 2 (MDM2) negative feedback loop, and is further enhanced by many types of post-translational modifications, such as phosphorylation, acetylation, sumoylation, ubiquitination, and methylation [4]
Two miRNAs, miR-25 and miR-30d, which directly interact with the 3 -UTR of the human TP53 mRNA [107] are downregulated in MM and their levels are inversely correlated to TP53 mRNA
Inactivation of the p53 pathway occurs in the majority of human cancers and usually confers resistance to therapy and poor survival
Summary
Since its discovery in 1979, the tumor suppressor protein p53 has been extensively studied. p53 is a transcription factor activated in response to several forms of cellular stress including DNA damage, hypoxia, viral infection, heat shock, and mitogenic or oncogenic stresses among others [1,2,3]. p53 pathway activation is mediated by the protein stabilization, via the disruption of a p53/murine double minute 2 (MDM2) negative feedback loop, and is further enhanced by many types of post-translational modifications, such as phosphorylation, acetylation, sumoylation, ubiquitination, and methylation [4]. It has been recently reported that biallelic inactivation of TP53 is more common in aggressive plasma cell neoplasms, and is frequently seen at relapse leading to rapid progression to plasma cell leukemia and/or extramedullary disease [16,49]. All these findings highlight the critical value of TP53 deletion and/or mutation in the pathogenesis of MM and reinforce the necessity of new therapeutic approaches for these high-risk patients
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