Role of T-Box Factors during Melanoma Progession

The malignant transformation of melanocytes starts with the acquisition of proliferative phenotype and inhibition of senescence, resulting in a radial growth phase melanoma (RGP). Although genetic mutations have been associated with this transformation process, little is known about the transition from RGP to an invasive vertical growth phase (VGP) melanoma during which malignant cells become competent for metastasis. Increasing evidence indicates that variation in the cellular microenvironment may playa critical role in the acquisition of an invasive phenotype, though few factors involved in this process have been identified to date. Here we investigate the role of the Tbx2 and Tbx3 transcription factors during melanoma progression. Both factors are over-expressed in melanoma cell lines, and Tbx2 can suppress senescence by repressing p21c1P1 expression in melanoma. We show that like Tbx2, Tbx3 may also work as an anti-senescence factor by binding the same target sequence and repressing p21c1P1 expression and that these transcription factors may bind as a complex to the p21c1P1 promoter with a factor recognising an Ebox adjacent to a half T-element. We also show that Tbx3 and Tbx2 contribute to melanoma invasiveness by modulating the expression of E-cadherin, a keratinocytemelanoma adhesion molecule whose loss is required for metastasis. Tbx2 and Tbx3 bind to the E-cadherin promoter and, surprisingly, are able either to repress or activate its expression depending on the cell line used. Preliminary results suggest that the histone tails, T-box factor-interacting proteins, and/or post-translational modification may modulate Tbx2 and Tbx3 DNA-binding ability in response to the cellular environment. Finally, since p21 c1P1 and E-cadherin expression are down-regulated during the RGP to VGP transition, we propose a model in which Tbx2 and Tbx3 playa dual role during this transition, working as anti-senescence and invasion-promoting factors in response to environmental cues.EThOS - Electronic Theses Online ServiceGBUnited Kingdo