New Perspectives on Melanoma_ The Role of PAX3

The second pathways activated by braf mutation is

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Unformatted text preview: when cells enter S‐phase [220]. Peak Pax3 expression lags behind Myc by a couple of hours, as expected for Myc‐regulated transcription of Pax3. In turn, Pax3 itself represses the activity of cell cycle regulatory genes Rb, Myc, and p21 by interacting with co‐repressor KAP1 [207]. Thus it appears that the levels of Pax3 may be regulated via a negative feedback loop, since Myc upregulates Pax3 which subsequently downregulates Myc. 45 Chapter II – Medic and Ziman, 2009 Additionally, two POU transcription factors, Brn­2 and Oct­1, are positive Pax3 transcriptional regulators [221,222]. Bound as a monomer Brn‐2 has a positive role in Pax3 expression in B16 (mouse melanoma cell line) cells, however when bound as a homodimer it decreases Pax3 expression [223]. In vitro experiments show BRN2 protein levels and DNA‐binding affinity decrease during melanocyte differentiation [16]. By contrast, OCT1 levels increase during the differentiation process [16] indicating that either BRN2 or OCT‐1 can regulate and maintain stable PAX3 levels. PAX3 expression in melanoma While PAX3 function in developing melanocytes is reasonably clear, its precise role in melanoma is undefined. Perplexingly, expression is observed in melanocytes of normal skin [17]; our own unpublished observations), in benign naevi [24] and in melanomas [21,23‐25,73,151]. In fact, PAX3 has been identified as a significant marker for melanoma staging [22,26] and for detection of circulating melanoma cells [22,224]. It has also been identified as an immunogenic protein in melanomas [157‐159], with several epitopes able to induce the host’s immune response ‐ stimulation of the immune response against PAX3‐expressing tumour cells results in tumour growth suppression [157,159]. Based on the information gleaned thus far it is clear that the function of PAX3 in melanoma is more than merely a marker of cell type. PAX3 role(s) in melanoma As in development, PAX3 plays an antiapoptotic role in cancers such as melanoma and paediatric rhabdomyosarcoma [155,156,160‐162]. Transfection with PAX3‐ specific antisense nucleotide (PAX3‐As) induces increased...
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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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