| Summary: | Skin melanocytes are cells that produce pigment in melanosomes and protect us from the damaging effects of UV radiation. This project covered two facets of melanocyte biology: melanocyte differentiation and transformation. Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder, is characterised by oculocutaneous albinism, a bleeding diathesis and other variable symptoms due to impaired formation of lysosome-related organelles, including melanosomes. We showed that cAMP agonists modestly restore pigmentation in HPS-mutant melanocytes and that this effect correlates with pigment formation in lysosomes instead of melanosomes, shown for the first time by colocalisation studies. These findings build upon our current understanding of melanosomal protein trafficking in HPS-mutant melanocytes and may have important implications for the treatment of hypopigmentation in patients with HPS or other forms of albinism. The other section of this project focused on melanoma. The majority of cancer cells have centrosome numerical abnormalities including extra or supernumerary centrosomes. This correlates with aneuploidy and genetic instability and may affect tumour aggressiveness and clinical outcome. The tumour suppressors p 15INK4B and p16INK4A (encoded by the familial melanoma CDKN2 locus) inhibit CDK4/6 activity and have important roles in cellular senescence. p 16INK4A and its downstream regulators are also associated with suppressing centrosome overduplication; however, the role of p15INK4B in centrosome amplification is unknown. We showed that normal human melanocyte lines did not exhibit centrosome number abnormalities whereas those from later stages of melanoma did. Additionally, under conditions of S-phase block, p 15INK4B and p 16INK4A status determined whether centrosome overduplication would occur. Indeed, removal of p 151NK4B from p 161NK4A negative cells from various stages of melanoma progression changed lines that previously would not overduplicate their centrosomes into cells that did. These data suggest that, during melanoma progression, sequential loss of p15INK4B and p16INK4A provides the conditions to deregulated centrosome duplication with consequences for genome instability,
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