Role of p53 family members p73 and p63 in human hematological malignancies

Abstract p53, mutated in over half of human cancers and about 13% of all hematological malignancies, maintains genomic integrity and triggers cellular senescence and apoptosis of damaged cells. In contrast to p53, the homologs p73 and p63 play critical roles in development of the central nervous sys...

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Bibliographic Details
Published in:Leukemia & lymphoma 2012-11, Vol.53 (11), p.2116-2129
Main Authors: Alexandrova, Evguenia M., Moll, Ute M.
Format: Article
Language:English
Subjects:
Animals
DNA Methylation
DNA-Binding Proteins - genetics
DNA-Binding Proteins - physiology
Humans
leukemia
Leukemia - etiology
Leukemia - genetics
lymphoma
Lymphoma - etiology
Lymphoma - genetics
Membrane Proteins - genetics
Membrane Proteins - physiology
methylation
Mice
myeloma
Nuclear Proteins - genetics
Nuclear Proteins - physiology
Promoter Regions, Genetic
Tumor Protein p73
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - physiology
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Summary:Abstract p53, mutated in over half of human cancers and about 13% of all hematological malignancies, maintains genomic integrity and triggers cellular senescence and apoptosis of damaged cells. In contrast to p53, the homologs p73 and p63 play critical roles in development of the central nervous system and skin/limbs, respectively. Moreover, dependent on the context they can exert tumor suppressor activities that cooperate with p53. Unlike p53, p73 and p63 are rarely mutated in cancers. Instead, up-regulation of the anti-apoptotic dominant-negative ΔNp73 and ΔNp63 isoforms is the most frequent abnormality in solid cancers. In hematological malignancies the most frequent p73 defect is promoter methylation and loss of expression, associated with unfavorable clinical outcomes. This suggests an essential tumor suppressor role of p73 in blood cells, also supported by genetic mouse models. Many therapeutic approaches aiming to restore p73 activity are currently being investigated. In contrast, the most frequent p63 abnormality is protein overexpression, associated with higher disease grade and poorer prognosis. Surprisingly, although available data are still scarce, the emerging picture is up-regulation of transactivation-competent TAp63 isoforms, suggesting a tumor-promoting role in this context.
ISSN:1042-8194
1029-2403
DOI:10.3109/10428194.2012.684348