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New Perspectives on Melanoma_ The Role of PAX3

J cellsci12139953999

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Unformatted text preview: se in phosphorylation at Ser209. Loss of phosphorylation at Ser209, consistent with a decrease in Pax3 expression, is observed after 4 hours of differentiation. The authors further suggest that the presence of a single phosphorylation at Ser201 after 8 hours of differentiation is sufficient to target Pax3 for degradation; which is an essential step for the progression of the differentiation program in activated satellite cells [218]. Transient Pax3 expression is observed in proliferative intermediate progenitor cell populations during satellite cell activation [337], but its sustained expression was 110 Chapter VI – Conclusion found to inhibit myogenic differentiation and maintain myogenic progenitors in an undifferentiated state [218]. Pax3 protein stability is regulated by the ubiquitin/proteasome system. Monobiquitination (at the two C‐terminal lysine residues, K475 and K437) by Taf1, targets Pax3 for proteasomal degradation, via Rad23B‐shuttling to the proteasome [218,338]. Interestingly the same two lysine residues, K475 and K437, have been recently shown to be critical for acetylation as well, associated with Pax3‐regulated neuronal differentiation [285]. Acetylated Pax3 may downregulate Hes1 and upregulate Neurog2, resulting in switching from stem cell proliferation to neuronal differentiation. Acetylated Pax3 is a substrate for NAD‐dependant deacetylase sirtuin 1 (SIRT1), associated with stem cell maintenance; and in the presence of SIRT1 Pax3 is deacetylated and thus able to activate Hes1 and repress Neurog2 transcription, maintaining undifferentiated cell state [285]. Pax3 deacetylation is also found to correlate with melanogenesis and possibly with melanocytic differentiation [339]. Histone deacetylase HDAC10 is found to physically interact with Pax3 via its paired domain, forming a ternary complex that maintains Pax3 in a deacetylated state; however, it is not clear if it actively deacetylates Pax3. HDAC10 decreases repressional activity of Pax3 and co...
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