Vinsamlegast notið þetta auðkenni þegar þið vitnið til verksins eða tengið í það: http://hdl.handle.net/1946/16907
Melanocytes are pigment producing cells, responsible for skin-, hair- and eye color. Microphthalmia-associated transcription factor, MITF, is a master regulator of melanocytes, regulating their development, function and survival. Hence, alterations of MITF result in changes in pigmentation but can also lead to severe pathologies such as melanoma, the cancer arising from melanocytes. MITF mutations have been identified in patients with hypopigmentation syndromes Waardenburg syndrome type 2A (WS2A) and Tietz syndrome (TS) as well as in patients with melanoma. Here, MITF mutations associated with WS2A, TS and melanoma were investigated in respect to their biochemical effects. The effects of these mutations on transcription activation potential of melanocyte-specific promoters, DNA-binding ability, nuclear localization and clonogenic potential were determined. The results suggest that most of the mutations associated with WS2A and TS fail to activate melanocyte-specific promoters and to bind DNA; nuclear localization was unaffected. Interestingly, some mutations behaved similarly to wild type MITF. Two of the mutations, R203K and S298P, are most likely neutral variants and not causative mutations of WS2A. Mutations associated with melanoma, behave very similar as wild type MITF regarding their transcription activation potential and DNA-binding ability. This study provides a first and important insight in how these mutations behave regarding their transcription activation potential and DNA binding.
We further investigate the role of IRF4, interferon regulatory factor 4, in pigmentation. Previous genome-wide association studies have associated a single nucleotide polymorphism in intron 4 of IRF4 with hair- and eye color, tanning ability and freckles. Also, it has been shown that IRF4 expression is activated by MITF. Here we show that MITF and IRF4 cooperate to activate expression of tyrosinase, the key enzyme in melanogenesis. This shows that IRF4 regulates human pigmentation by cooperating with MITF in order to activate TYR expression.
Keywords: MITF, pigmentation, Waardenburg syndrome, melanoma and IRF4
|Christine Grill thesis for Skemman.pdf||32.03 MB||Opinn||Heildartexti||Skoða/Opna|