Insights into the Role of PAX-3 in the Development of Melanocytes and Melanoma

Abstract

Melanoma is the deadliest form of skin cancer in the United States with an increasing prevalence. However, the development of melanoma from a melanocyte precursor is still poorly defined. Understanding the molecules responsible for melanoma progression may lead to improved targeted therapy. One potential molecule is the paired box-3 (PAX-3) protein, which has been implicated in the development of melanocytes and malignant melanoma. In melanoma, the expression of PAX-3 is believed to be differentially regulated, and has been linked with malignancies and staging of the disease. The loss of PAX-3 regulation has also been associated with the loss of transforming growth factor-beta (TGF-β) activity, but its effect on PAX-3 in differentiated melanocytes as well as metastatic melanoma remains unclear. Understanding PAX-3 regulation could potentially shift melanoma to a less aggressive and less metastatic disease. This review summarizes our current knowledge on PAX-3 during melanocyte development, its regulation, and its implications in the development of novel chemo-immunotherapeutics against metastatic melanoma.

Keywords: MITF; PAX-3; SOX10; TGF-β; UVR; melanocyte; melanoma.

Fig. (1)

Possible role of PAX-3 in melanocytogenesis. (A) During melanocytogenesis, PAX-3 forms a complex with SOX10 to activate MITF. MITF then binds to the DCT promoter to allow the melanocyte to differentiate. However, PAX-3 can also compete with MITF in binding to DCT, and thus inhibiting it. (B) In the presence of β-catenin, the action of PAX-3 to block DCT transcription is lost. DCT then contributes to melanocyte differentiation.

Fig. (2)

Ultra-violet irradiation and melanocyte differentiation. During normal melanocyte function, keratinocytes in the dermal layer of the skin produce TGF-β that binds to the RI–RII receptor on the surface of melanocytes. This binding may signal phosphorylated R-Smad to form a complex with Smad4 and Ski, which inhibits the transcription of PAX-3. However, when UV irradiation stimulates keratinocytes, both JNK and phosphorylated p53 respond by activating AP-1, which negatively regulates TGF-β. Phosphorylated p53 also induces POMC/MSH expression that allows αMSH to be secreted for binding to the MC1R on the cell surface of melanocytes. MC1R, with the aid of adenylate cyclase, activates the cAMP pathway to phosphorylate CREB, which allows PAX-3 and SOX10 to bind together and induce MITF transcription. MITF then induces the transcription of the downstream targets TYR, TRP-1, and Dct, which are indications of melanocyte differentiation. Both MITF and PAX-3 can also activate MET, a protein that has been implicated in melanoma metastasis.