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Melanocyte transformation requires complete loss of all pocket protein function via a mechanism that mitigates the need for MAPK pathway activation

Tonks, ID, Mukhopadhyay, P, Schroder, WA, Sorolla, A, Mould, AW, Handoko, HY, Ferguson, B, Muller, HK, Keith, P, Hayward, NK, Walker, GJ and Kay, GF 2017 , 'Melanocyte transformation requires complete loss of all pocket protein function via a mechanism that mitigates the need for MAPK pathway activation' , Oncogene, vol. 36, no. 26 , pp. 3789-3795 , doi: 10.1038/onc.2016.511.

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Abstract

Deregulation of p16INK4A is a critical event in melanoma susceptibility and progression. It is generally assumed that the major effect of loss of p16 function is mediated through the CDK-cyclin pathway via its influence on the pocket protein (PP) pRb. However, there are also two other PPs, p107 and p130, which, when phosphorylated by CDK-cyclin complexes, play a role in permitting cell progression. Cohorts of mice carrying melanocyte-specific knockouts (KOs) of various combinations of the three PPs were generated. Mice null for pRb, p107, p130 or any combination of double mutants did not develop melanoma. Surprisingly, melanocyte-specific loss of all three PPs facilitated melanoma development (median age of onset 308 days, penetrance 40% at 1 year). Tumorigenesis was exacerbated by Trp53 co-deletion (median age of onset 275 days, penetrance 82% at 1 year), with cell culture studies indicating that this difference may result from the apoptotic role of Trp53. Melanomas in PP;Trp53-deficient mice lacked either Ras or Braf mutations, and hence developed in the absence of constitutive MAPK pathway activation. The lag period between induction of total PP or PP/Trp53 KO and melanoma development indicates that additional genetic or epigenetic alterations may account for neoplastic progression. However, exome sequencing of PP;Trp53 KO melanomas failed to reveal any additional recurrent driver mutations. Analysis of the putative mutation signature of the PP;Trp53 KO melanomas suggests that melanocytes are primed for transformation via a mutagenic mechanism involving an excess of T > G substitutions, but not involving a preponderance of C > T substitutions at CpG sites, which is the case for most spontaneous cancers not driven by a specific carcinogen. In sum, deregulation of all three PPs appears central to neoplastic progression for melanoma, and the customary reference to the p16 INKA /CDK4/pRB pathway may no longer be accurate; all PPs are potentially critical targets of CDK-cyclins in melanoma.

Item Type: Article
Authors/Creators:Tonks, ID and Mukhopadhyay, P and Schroder, WA and Sorolla, A and Mould, AW and Handoko, HY and Ferguson, B and Muller, HK and Keith, P and Hayward, NK and Walker, GJ and Kay, GF
Journal or Publication Title: Oncogene
Publisher: MacMillan Press
ISSN: 0950-9232
DOI / ID Number: 10.1038/onc.2016.511
Copyright Information:

© 2017 Macmillan Publishers Limited

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