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p53 Information
mdm family
mouse models
ASPP family
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Inactivating p53 pathway in cancer
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More information on p53 mutations and specific types of cancer can be found here
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Heterogeneity of p53 inactivation in human cancer. 1- p53 mutations can be found in 50% of human cancers, but their penetrance is highly heterogeneous, as reflected by the diverse remaining transactivation activity that ranges from O to 100%. 2- Various DNA viruses, such as SV40, HPV or adenoviruses, encode proteins that target p53 protein. 3- In inflammatory breast cancer and neuroblastoma, p53 is predominantly found in the cytoplasm. 4- mdm2 accumulation is found in numerous cancers, such as sarcoma or breast carcinomas. 5- PTEN, a p53 regulated gene, is mutated in various types of cancer including glioblastoma. 6- Although no mutation of AKT has been found in human cancer, constitutive activation of its kinase activity has been observed via deregulation of the upstream pathway. 7- Mutations in various pathways upstream of p53 (ATM, p19ARF or Hcdk2 gene) can be observed in various types of cancer.
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p53 Mutation
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Inactivation of the p53 gene is essentially due to small mutations (missense and nonsense mutations or insertions/deletions of several nucleotides), which lead to either expression of a mutant protein (90% of cases) or absence of protein (10% of cases)(see the special issue of Human Mutation devoted to p53 published in January 2002 for more information). No inactivation of p53 gene expression by hypermethylation of transcription promoters has been demonstrated at the present time, which supports the hypothesis of a function for p53 mutants. |
HPV Infection
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The E6 viral protein expressed by HPV specifically binds to the p53 protein and induces its degradation (Scheffner et al., 1990). This observation explains the rarity of p53 mutations in cervical cancers (Crook et al., 1992). p53 inactivation by a viral protein has not been formally demonstrated in other human cancers associated with viral infection, such as HCC (associated with HBV) or Burkitt lymphoma (associated with EBV). |
Nuclear exclusion
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In inflammatory breast cancers or neuroblastomas, molecular and immunohistochemical analyses demonstrate accumulation of wild-type p53 in the cytoplasm of tumour cells, leading to functional inactivation of p53 (Moll et al., 1995; Moll et al., 1996; Moll et al., 1992).
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MMD2 Amplification
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The mdm2 protein regulates the stability of the p53 protein by ubiquitination and transport towards the proteasome (Iwakuma and Lozano, 2003; Moll and Petrenko, 2003). Abnormal accumulation of the mdm2 protein is observed in many tumours, especially sarcomas (Onel and Cordon-Cardo, 2004). This accumulation can be due to amplification of the mdm2 gene, enhanced transcription of the gene or enhanced translation of its messenger RNA (Michael and Oren, 2002). Although these tumours would be expected to no longer express p53, the opposite situation is generally observed, with a large number of tumours overexpressing both p53 and mdm2. The reasons for this apparent paradox have not been elucidated. No formal exclusion between p53 gene mutation and mdm2 accumulation has been clearly demonstrated, suggesting that this situation could be due to an oncogenic activity of mdm2 independent of p53. |
PTEN mutations
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AKT kinase phosphorylates mdm2 protein and induces its migration into the nucleus where it binds and ubiquinates p53. Upon growth factor activation, mdm2 activation through AKT activation ensure proper cell growth.
PTEN, a p53 regulated gene, down regulate the AKT pathway.
PTEN deletion leads to an increase of AKT activity, an increase of nuclear mdm2 and impairs p53 response |
AKT Alterations
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AKT kinase phosphorylates mdm2 protein and induces its migration into the nucleus where it binds and ubiquinates p53. Upon growth factor activation, mdm2 activation through AKT activation ensure proper cell growth.
PTEN, a p53 regulated gene, down regulate the AKT pathway.
Although no mutation of AKT has been found in human cancer, constitutive activation of its kinase activity has been observed via deregulation of the upstream pathway. An increase of AKT activity lead to an increase of nuclear mdm2 and impairs p53 response |
Upstream signaling
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At G1, as a consequence of DNA damage induced by gamma radiation, activated ATM phosphorylates p53 on Ser15, CHK2 on Thr68, and MDM2 on Ser395. Subsequently, activated CHK2 phosphorylates p53 on Ser20. Together, these phosphorylations interfere with p53 binding to MDM2, leading to stabilization and activation of p53.
Mutations of ATM in AT patients or in T-cell leukaemia impair the p53 response after gamma radiation
Mutations of CHK2 are found in Li-Fraumeni like families.
The function of CHK2 in this pathway has been recently questioned and remains controversial. |
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