Tyrosinase Gene Expression is Regulated by p53

Abstract

Tyrosinase, the rate-limiting enzyme for melanin synthesis, is induced after ultraviolet irradiation as part of the tanning response, the major recognized photoprotective response of human skin. Other DNA-damaging agents and DNA fragments such as thymidine dinucleotides also induce tyrosinase gene expression. Moreover, like ultraviolet light they also activate p53. To determine whether p53 activation is required for this increased tyrosinase expression, we employed two experimental systems: (i) a human melanoma line (WM35) known to express wild-type p53 versus WM35 cells engineered to express a transcriptionally inactive dominant-negative p53 (WM35-p53DN) or the empty vector alone (WM35-pCMV7) and (ii) mice with wild-type p53 versus p53 knockout mice. In WM35-p53DN cells, the baseline p53 protein level was higher than in WM35 or WM35-pCMV7 cells, and tyrosinase transcripts were lower. After ultraviolet irradiation, in all cell lines the p53 protein level increased within the first 24 h, as expected; and at 24 h tyrosinase mRNA levels were decreased. Consistent with the literature, these data in combination suggest that increased p53 protein level downregulates tyrosinase mRNA. In WM35 and WM35-pCMV7 cells at 48 and 72 h, however, whereas p53 levels remained elevated, tyrosinase mRNA levels compared to pre-irradiation levels tripled, whereas in WM35-p53DN cells levels remained below baseline. In thymidine-dinucleotide-treated WM35 and WM35-pCMV7 cells there was a comparable upregulation of tyrosinase mRNA within 24 h that persisted through 72 h, but there was no upregulation of tyrosinase mRNA in WM35-p53DN cells any time after ultraviolet irradiation or thymidine dinucleotide treatment. In ear skin of p53 wild-type mice, topical application of thymidine dinucleotide induced a 4-5-fold increase in epidermal melanin content after 3 wk, but in p53 knockout mice thymidine dinucleotide application caused no detectable increase in melanin. Together, these data demonstrate that p53 activation increases tyrosinase mRNA level and subsequently pigmentation. The data further suggest that tanning is part of a p53-mediated adaptive response of mammalian skin to DNA damage from ultraviolet irradiation.

Ultraviolet radiation and cutaneous malignant melanoma

“…Tyrosinase can be induced after UV radiation in a p53-dependent manner (Nylander et al, 2000;Khlgatian et al, 2002), and tyrosinase activity is increased in G2-arrested melanoma cells, as is a-MSH expression (Wong et al, 1974;McLane and Pawelek, 1988;Chakraborty et al, 1999). These results support a profound role for p53 in the response of melanocytes to UV damage, permitting cells to pause in the cell cycle to repair or die, yet simultaneously encouraging melanin synthesis and increased differentiation.…”

“…Melanin, a brown-black pigment, is synthesized in melanosomes within epidermal melanocytes, and then distributed to surrounding keratinocytes through melanocytic dendritic processes (reviewed by Hearing, 1999). Melanin can absorb UV photons and free radicals induced by UV before they interact with other cellular components (Kawada et al, 1994;Khlgatian et al, 2002;Ortonne, 2002). The highly organized presentation of melanosomes throughout the epidermis, characteristic of dark-colored skin, is reminiscent of a highly protective screen designed to absorb and scatter damaging UV radiation.…”

Alpha-Melanocyte–Stimulating Hormone Suppresses Oxidative Stress through a p53-Mediated Signaling Pathway in Human Melanocytes

“…Our results unraveled a mechanism involving a-MSH and p53 in the adaptive response of melanocytes to UVR. Others have shown that p53 increases the expression of the melanogenic enzymes tyrosinase and tyrosine-related protein 1 (TYRP-1), suggesting its role in regulating melanogenesis (20,21). In mouse skin, p53 stimulates the expression of proopiomelanocortin (POMC), the precursor of a-MSH and adrenocorticotropic hormone (ACTH; refs.…”

P53 sous le soleil

“…La capacité de pigmentation de ces unités apparaît donc étroitement liée à la réponse des kératinocytes aux UV. Dans les mélanocytes, il a été montré que la transcription du gène codant pour l'enzyme clé de la mélanogenèse (la tyrosinase) est aussi stimulée par l'exposition aux UV [13].…”