New Perspectives on Melanoma_ The Role of PAX3


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Unformatted text preview: Dct promoter and blocks its activation by Mitf [19], but still retains moderate activation of Mitf to maintain intermediate protein levels required for melanoblast proliferation; it could also be involved in migration and survival of undifferentiated committed melanoblasts. In melanocytes however, it shows 43 Chapter II – Medic and Ziman, 2009 preferential binding to both components of the differentiation pathway, i.e. MITF and TRP­1 [16], where it maintains melanocyte cell function. These results support the idea that PAX3 has different role/s at different stages of melanocyte development. Regulation of Pax3 function Another mechanism by which functional switching of Pax3 occurs is via modulation of protein activity by cell cycle regulator pRB (retinoblastoma protein) [212]. pRB family proteins have a dual role in both cell cycle regulation, and in cell fate determination [212]. As a check point in the cell cycle, pRB acts as a negative regulator by complexing with and inactivating E2F family members, repressing their transcriptional function [213‐215] thus preventing cell cycle progression. Secondly, as a determinant of cell fate, active unphosphorylated pRB forms a stable complex with Pax3, repressing its transcriptional activity [212]. The implications of this are that pRB repression of E2F transcriptional activity facilitates cell cycle exit, and pRB repression of Pax3 transcriptional activity enables terminal differentiation (by reducing levels of active Pax3 protein, thus allowing accumulated Mitf to activate Dct expression and induce rapid terminal differentiation) or apoptosis (due to an antiapoptotic role of Pax3). In other words during cell proliferation active Pax3 protein levels are maintained. Upon exiting the cell cycle however, Pax3 activity as an inhibitor of terminal differentiation is suppressed, allowing the cell cycle to proceed. Pax3 protein activity may also be regulated by phosphorylation and ubiquitination. A Ser205 phosphorylation site has recently been identified; but...
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This document was uploaded on 03/06/2014 for the course CHEMISTRY 12 at National University of Singapore.

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