New Perspectives on Melanoma_ The Role of PAX3

Presumablypax3isalsoimportantforthe

Info icon This preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: in maintaining committed progenitor cells is similarly observed in other Pax3‐dependant lineages, namely in neuronal [122] and myogenic (reviewed in [15]) lineages. In regulating neuronal precursors, Pax3 plays a dual role: at early stages of development it acts to maintain “stemness” of migratory neural cells, via the repressor Hes1. Later it initiates neuronal lineage specification via the proneural activator Ngn2 [122]. Hes1, is also implicated in maintenance of both embryonic melanoblasts and melanocyte stem cells in the bulge area of adult mouse hair follicles, possibly via Pax3 [194]. The pathways by which Pax3 maintains “stemness” have been detailed for melanocyte stem cells of the bulge area of the adult mouse hair follicle. Pax3 inhibits differentiation by binding to the Dct promoter acting to repress Dct. Grg4 (Groucho co‐repressor) is also required for this interaction; it physically binds both Pax3 and Lef1 to forms a complex on the Dct promoter. Lef1 is also a cofactor for β‐catenin (activated by Wnt signalling), which displaces Grg4 together with Pax3, allowing Mitf to bind to the response element within the Dct promoter. Pax3 has a higher affinity for the Dct promoter, thus replacing Mitf when present at equal or higher concentrations [19]. Mitf binding to Dct and other genes encoding enzymes for melanin synthesis Tyr, TRP­1 initiates the melanogenic cascade. Thus Pax3 acts as a molecular switch to direct this process by binding either to the Dct promoter to inhibit differentiation or to the Mitf promoter in synergy with Sox10 to activate Mitf transcription [64,65,67] and the differentiation pathway. In fact, Pax3 plays an even more complex role in regulation of melanocyte differentiation; Pax3 also has the ability to directly bind to and positively regulate the TRP­1 promoter [73,74] thus enhancing the melanogenic cascade. In summary, Pax3 interacts with distinct recognition motifs found in the promoters of MITF, 40 Chapter II – Medic and Ziman, 2009 TRP­1 a...
View Full Document

{[ snackBarMessage ]}

What students are saying

  • Left Quote Icon

    As a current student on this bumpy collegiate pathway, I stumbled upon Course Hero, where I can find study resources for nearly all my courses, get online help from tutors 24/7, and even share my old projects, papers, and lecture notes with other students.

    Student Picture

    Kiran Temple University Fox School of Business ‘17, Course Hero Intern

  • Left Quote Icon

    I cannot even describe how much Course Hero helped me this summer. It’s truly become something I can always rely on and help me. In the end, I was not only able to survive summer classes, but I was able to thrive thanks to Course Hero.

    Student Picture

    Dana University of Pennsylvania ‘17, Course Hero Intern

  • Left Quote Icon

    The ability to access any university’s resources through Course Hero proved invaluable in my case. I was behind on Tulane coursework and actually used UCLA’s materials to help me move forward and get everything together on time.

    Student Picture

    Jill Tulane University ‘16, Course Hero Intern