New Perspectives on Melanoma_ The Role of PAX3


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Unformatted text preview: vide here a comprehensive consideration of the significance of PAX3 expression in melanoma. PAX3 and Pax3 indicate human and mouse transcription factor respectively. Key words: Pax genes; melanocytes; melanoblasts; melanocyte stem cells; MITF; melanoma 32 Chapter II – Medic and Ziman, 2009 Introduction Cutaneous Malignant Melanoma is the most aggressive form of skin cancer, thought to be derived from cutaneous melanocytes. Its aggressiveness is attributed to frequent metastasis and high drug resistance. Intensive research of the mechanisms regulating melanoma tumourigenesis has included investigation of the factors and pathways of normal melanocyte development and function. One key factor is the developmental transcriptional regulator PAX3. PAX3/Pax3 (PAX3 and Pax3 indicate human and mouse transcription factor respectively) is a member of the Pax family of transcription factors which are highly conserved throughout phylogeny. All play a crucial role in embryogenesis but are also implicated in tumourigenesis (for reviews see [13,14,52,53,169‐171]). Pax3 protein contains two DNA binding domains, a paired domain and a homeodomain which can be utilised alone or in combination to bind downstream target genes [76,172‐174]. In addition Pax3 contains a C‐terminal transcription activation domain and an octapeptide [173,175,176]. The ability of Pax3 to employ one or both DNA binding domains accounts for its ability to regulate a variety of downstream targets. Moreover, a single Pax3 gene encodes multiple transcripts produced by alternate splicing (Figure 2.1) [11,151,168,177]. The resultant protein isoforms provide functional diversity for Pax3, as they differ in structure and ultimately in activity of their paired, homeodomain and alternate transactivation domains [177‐179]. Even though Pax3 is recognised as a key embryonic regulator of melanocyte specification and development, its expression and function in differentiated epidermal melanocytes of adult human skin is uncertain and its role in...
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