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• W2109349283 abstract "UV-induced pigmentation (suntanning) requires induction of α-melanocyte-stimulating hormone (α-MSH) secretion by keratinocytes. α-MSH and other bioactive peptides are cleavage products of pro-opiomelanocortin (POMC). Here we provide biochemical and genetic evidence demonstrating that UV induction of POMC/MSH in skin is directly controlled by p53. Whereas p53 potently stimulates the POMC promoter in response to UV, the absence of p53, as in knockout mice, is associated with absence of the UV-tanning response. The same pathway produces β-endorphin, another POMC derivative, which potentially contributes to sun-seeking behaviors. Furthermore, several instances of UV-independent pathologic pigmentation are shown to involve p53 “mimicking” the tanning response. p53 thus functions as a sensor/effector for UV pigmentation, which is a nearly constant environmental exposure. Moreover, this pathway is activated in numerous conditions of pathologic pigmentation and thus mimics the tanning response. UV-induced pigmentation (suntanning) requires induction of α-melanocyte-stimulating hormone (α-MSH) secretion by keratinocytes. α-MSH and other bioactive peptides are cleavage products of pro-opiomelanocortin (POMC). Here we provide biochemical and genetic evidence demonstrating that UV induction of POMC/MSH in skin is directly controlled by p53. Whereas p53 potently stimulates the POMC promoter in response to UV, the absence of p53, as in knockout mice, is associated with absence of the UV-tanning response. The same pathway produces β-endorphin, another POMC derivative, which potentially contributes to sun-seeking behaviors. Furthermore, several instances of UV-independent pathologic pigmentation are shown to involve p53 “mimicking” the tanning response. p53 thus functions as a sensor/effector for UV pigmentation, which is a nearly constant environmental exposure. Moreover, this pathway is activated in numerous conditions of pathologic pigmentation and thus mimics the tanning response. Ultraviolet radiation (UV) represents a definitive risk factor for skin cancer, especially when exposure occurs in combination with certain underlying genetic traits such as red hair and fair skin (Fitzpatrick and Sober, 1985Fitzpatrick T.B. Sober A.J. Sunlight and skin cancer.N. Engl. J. Med. 1985; 313: 818-820Crossref PubMed Scopus (47) Google Scholar, Holick, 2001Holick M.F. Sunlight “D”ilemma: risk of skin cancer or bone disease and muscle weakness.Lancet. 2001; 357: 4-6Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). Pigmentation of the skin results from the synthesis of melanin in the pigment-producing cells, the melanocytes, followed by distribution and transport of pigment granules to neighboring keratinocytes. It is commonly believed that melanin is crucial for absorption of free radicals that have been generated within the cytoplasm by UV, and it acts as a direct shield from UV and visible light radiation (Pathak and Fanselow, 1983Pathak M.A. Fanselow D.L. Photobiology of melanin pigmentation: dose/response of skin to sunlight and its contents.J. Am. Acad. Dermatol. 1983; 9: 724-733Abstract Full Text PDF PubMed Scopus (92) Google Scholar, Riley, 1997Riley P.A. Melanin.Int. J. Biochem. Cell Biol. 1997; 29: 1235-1239Crossref PubMed Scopus (513) Google Scholar, Bykov et al., 2000Bykov V.J. Marcusson J.A. Hemminki K. Effect of constitutional pigmentation on ultraviolet B-induced DNA damage in fair-skinned people.J. Invest. Dermatol. 2000; 114: 40-43Crossref PubMed Scopus (35) Google Scholar). Molecular and genetic data indicate that variations in the coding region of the melanocortin-1-receptor (MC1R) play an important role in tanning and pigmentation in humans (Valverde et al., 1995Valverde P. Healy E. Jackson I. Rees J.L. Thody A.J. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans.Nat. Genet. 1995; 11: 328-330Crossref PubMed Scopus (796) Google Scholar). MC1R is expressed in melanocytes and is activated by its ligand α-melanocyte-stimulating hormone (α-MSH). This propigmentation hormone is produced and secreted following UV by both keratinocytes and melanocytes in the skin (Schauer et al., 1994Schauer E. Trautinger F. Kock A. Schwarz A. Bhardwaj R. Simon M. Ansel J.C. Schwarz T. Luger T.A. Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes.J. Clin. Invest. 1994; 93: 2258-2262Crossref PubMed Scopus (310) Google Scholar, Chakraborty et al., 1996Chakraborty A.K. Funasaka Y. Slominski A. Ermak G. Hwang J. Pawelek J.M. Ichihashi M. Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture: regulation by ultraviolet B.Biochim. Biophys. Acta. 1996; 1313: 130-138Crossref PubMed Scopus (287) Google Scholar). The gene encoding α-MSH is pro-opiomelanocortin (POMC), a multicomponent precursor for α-MSH (melanotropic), ACTH (adrenocorticotropic), and the opioid peptide β-endorphin. Normal synthesis of α-MSH and ACTH is an important determinant of constitutive human pigmentation and the cutaneous response to UV (Lunec et al., 1990Lunec J. Pieron C. Sherbet G.V. Thody A.J. Alpha-melanocyte-stimulating hormone immunoreactivity in melanoma cells.Pathobiology. 1990; 58: 193-197Crossref PubMed Scopus (54) Google Scholar, Chakraborty et al., 1996Chakraborty A.K. Funasaka Y. Slominski A. Ermak G. Hwang J. Pawelek J.M. Ichihashi M. Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture: regulation by ultraviolet B.Biochim. Biophys. Acta. 1996; 1313: 130-138Crossref PubMed Scopus (287) Google Scholar, Kippenberger et al., 1996Kippenberger S. Bernd A. Bereiter-Hahn J. Ramirez-Bosca A. Kaufmann R. Holzmann H. Transcription of melanogenesis enzymes in melanocytes: dependence upon culture conditions and co-cultivation with keratinocytes.Pigment Cell Res. 1996; 9: 179-184Crossref PubMed Scopus (24) Google Scholar) since mutations in the POMC gene result in a red-hair phenotype (like that of MC1R alleles) in addition to metabolic abnormalities, such as adrenal insufficiency and obesity (Krude et al., 1998Krude H. Biebermann H. Luck W. Horn R. Brabant G. Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans.Nat. Genet. 1998; 19: 155-157Crossref PubMed Scopus (1313) Google Scholar). Several independent reports have demonstrated synthesis of α-MSH and ACTH by epidermal keratinocytes and melanocytes (Iyengar, 1994Iyengar B. Expression of proliferating cell nuclear antigen (PCNA): proliferative phase functions and malignant transformation of melanocytes.Melanoma Res. 1994; 4: 293-295Crossref PubMed Scopus (11) Google Scholar, Schauer et al., 1994Schauer E. Trautinger F. Kock A. Schwarz A. Bhardwaj R. Simon M. Ansel J.C. Schwarz T. Luger T.A. Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes.J. Clin. Invest. 1994; 93: 2258-2262Crossref PubMed Scopus (310) Google Scholar, Schwarz et al., 1995Schwarz A. Bhardwaj R. Aragane Y. Mahnke K. Riemann H. Metze D. Luger T.A. Schwarz T. Ultraviolet-B-induced apoptosis of keratinocytes: evidence for partial involvement of tumor necrosis factor-alpha in the formation of sunburn cells.J. Invest. Dermatol. 1995; 104: 922-927Crossref PubMed Scopus (245) Google Scholar, Gilchrest et al., 1996Gilchrest B.A. Park H.Y. Eller M.S. Yaar M. Mechanisms of ultraviolet light-induced pigmentation.Photochem. Photobiol. 1996; 63: 1-10Crossref PubMed Scopus (299) Google Scholar, Wintzen et al., 1996Wintzen M. Yaar M. Burbach J.P. Gilchrest B.A. Proopiomelanocortin gene product regulation in keratinocytes.J. Invest. Dermatol. 1996; 106: 673-678Crossref PubMed Scopus (122) Google Scholar, Tsatmali et al., 2000Tsatmali M. Ancans J. Yukitake J. Thody A.J. Skin POMC peptides: their actions at the human MC-1 receptor and roles in the tanning response.Pigment Cell Res. 2000; 13: 125-129Crossref PubMed Scopus (47) Google Scholar, D'Orazio et al., 2006D'Orazio J.A. Nobuhisa T. Cui R. Arya M. Spry M. Wakamatsu K. Igras V. Kunisada T. Granter S.R. Nishimura E.K. et al.Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning.Nature. 2006; 443: 340-344Crossref PubMed Scopus (250) Google Scholar), and the cutaneous α-MSH content showed little change after hypophysectomy (Eberle, 1998Eberle A. The Melanotropins. Karger, Basel, Switzerland1998Google Scholar). When taken together with the fact that circulating levels of α-MSH and ACTH are low in humans, these findings suggest that cutaneous activity of these two hormones might involve primarily local paracrine, or perhaps autocrine, effects within the epidermis (Abdel-Malek et al., 2000Abdel-Malek Z. Scott M.C. Suzuki I. Tada A. Im S. Lamoreux L. Ito S. Barsh G. Hearing V.J. The melanocortin-1 receptor is a key regulator of human cutaneous pigmentation.Pigment Cell Res. 2000; 13: 156-162Crossref PubMed Scopus (112) Google Scholar, Tsatmali et al., 2000Tsatmali M. Ancans J. Yukitake J. Thody A.J. Skin POMC peptides: their actions at the human MC-1 receptor and roles in the tanning response.Pigment Cell Res. 2000; 13: 125-129Crossref PubMed Scopus (47) Google Scholar). Although expression of POMC/α-MSH is critical for the UV-photopigmentation response, the underlying mechanism of UV-mediated expression of α-MSH is not known. The tumor-suppressor protein p53 (Lane and Crawford, 1979Lane D.P. Crawford L.V. T antigen is bound to a host protein in SV40-transformed cells.Nature. 1979; 278: 261-263Crossref PubMed Scopus (1691) Google Scholar, Linzer and Levine, 1979Linzer D.I. Levine A.J. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells.Cell. 1979; 17: 43-52Abstract Full Text PDF PubMed Scopus (1188) Google Scholar) is a transcription factor that plays a pivotal role in the cellular response to genotoxic stressors such as UV and chemically induced DNA damage (Fields and Jang, 1990Fields S. Jang S.K. Presence of a potent transcription activating sequence in the p53 protein.Science. 1990; 249: 1046-1049Crossref PubMed Scopus (641) Google Scholar, Farmer et al., 1992Farmer G. Bargonetti J. Zhu H. Friedman P. Prywes R. Prives C. Wild-type p53 activates transcription in vitro.Nature. 1992; 358: 83-86Crossref PubMed Scopus (503) Google Scholar). It has been shown to directly activate transcription of numerous genes such as those that regulate cell-cycle progression, apoptotic cellular pathways, and others (Levine et al., 2006Levine A.J. Hu W. Feng Z. The P53 pathway: what questions remain to be explored?.Cell Death Differ. 2006; 13: 1027-1036Crossref PubMed Scopus (505) Google Scholar). Loss of function of p53 leads to aberrant cell growth and survival responses and, as such, p53 dysregulation plays an integral part in the genesis of human cancer. In the skin, p53 function is critical for the retention of tissue integrity following UV irradiation. p53−/− mice exhibited an enormously enhanced propensity to develop tumors following UVB by week 16, while none of the comparably treated p53+/+ mice developed skin tumors after 17 weeks (Li et al., 1998Li G. Tron V. Ho V. Induction of squamous cell carcinoma in p53-deficient mice after ultraviolet irradiation.J. Invest. Dermatol. 1998; 110: 72-75Crossref PubMed Scopus (81) Google Scholar). UV can induce “signature” mutations in the p53 gene, which are almost exclusively dipyrimidine C to T substitutions that include CC to TT frameshift mutations; these are rarely seen in noncutaneous tumors (Brash et al., 1991Brash D.E. Rudolph J.A. Simon J.A. Lin A. McKenna G.J. Baden H.P. Halperin A.J. Ponten J. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma.Proc. Natl. Acad. Sci. USA. 1991; 88: 10124-10128Crossref PubMed Scopus (1645) Google Scholar, Ananthaswamy et al., 1997Ananthaswamy H.N. Loughlin S.M. Cox P. Evans R.L. Ullrich S.E. Kripke M.L. Sunlight and skin cancer: inhibition of p53 mutations in UV-irradiated mouse skin by sunscreens.Nat. Med. 1997; 3: 510-514Crossref PubMed Scopus (190) Google Scholar). These mutations were found in the skin of UV-irradiated mice months before tumor development (Ananthaswamy et al., 1997Ananthaswamy H.N. Loughlin S.M. Cox P. Evans R.L. Ullrich S.E. Kripke M.L. Sunlight and skin cancer: inhibition of p53 mutations in UV-irradiated mouse skin by sunscreens.Nat. Med. 1997; 3: 510-514Crossref PubMed Scopus (190) Google Scholar). Conversely, mutations in p53 are absent from most melanomas (Lubbe et al., 1994Lubbe J. Reichel M. Burg G. Kleihues P. Absence of p53 gene mutations in cutaneous melanoma.J. Invest. Dermatol. 1994; 102: 819-821Abstract Full Text PDF PubMed Google Scholar). In addition to the above activities, p53 has been shown to be essential for the formation of “sunburn cells,” which are a hallmark of sunburns (Ziegler et al., 1994Ziegler A. Jonason A.S. Leffell D.J. Simon J.A. Sharma H.W. Kimmelman J. Remington L. Jacks T. Brash D.E. Sunburn and p53 in the onset of skin cancer.Nature. 1994; 372: 773-776Crossref PubMed Scopus (1302) Google Scholar). These apoptotic keratinocytes are absent in p53−/− mice following UV irradiation. This important discovery provided a striking example of p53's pivotal role in regulating keratinocyte apoptosis in the context of a naturally occurring environmental exposure. Collectively, these observations led us to examine the possibility that p53 may also participate in regulation of the pigmentation response to UV. Previous data had suggested that the POMC gene is upregulated at both protein and mRNA levels following UV irradiation of skin (Iyengar, 1994Iyengar B. Expression of proliferating cell nuclear antigen (PCNA): proliferative phase functions and malignant transformation of melanocytes.Melanoma Res. 1994; 4: 293-295Crossref PubMed Scopus (11) Google Scholar, Schauer et al., 1994Schauer E. Trautinger F. Kock A. Schwarz A. Bhardwaj R. Simon M. Ansel J.C. Schwarz T. Luger T.A. Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes.J. Clin. Invest. 1994; 93: 2258-2262Crossref PubMed Scopus (310) Google Scholar, Schwarz et al., 1995Schwarz A. Bhardwaj R. Aragane Y. Mahnke K. Riemann H. Metze D. Luger T.A. Schwarz T. Ultraviolet-B-induced apoptosis of keratinocytes: evidence for partial involvement of tumor necrosis factor-alpha in the formation of sunburn cells.J. Invest. Dermatol. 1995; 104: 922-927Crossref PubMed Scopus (245) Google Scholar, Gilchrest et al., 1996Gilchrest B.A. Park H.Y. Eller M.S. Yaar M. Mechanisms of ultraviolet light-induced pigmentation.Photochem. Photobiol. 1996; 63: 1-10Crossref PubMed Scopus (299) Google Scholar, Wintzen et al., 1996Wintzen M. Yaar M. Burbach J.P. Gilchrest B.A. Proopiomelanocortin gene product regulation in keratinocytes.J. Invest. Dermatol. 1996; 106: 673-678Crossref PubMed Scopus (122) Google Scholar, Tsatmali et al., 2000Tsatmali M. Ancans J. Yukitake J. Thody A.J. Skin POMC peptides: their actions at the human MC-1 receptor and roles in the tanning response.Pigment Cell Res. 2000; 13: 125-129Crossref PubMed Scopus (47) Google Scholar, D'Orazio et al., 2006D'Orazio J.A. Nobuhisa T. Cui R. Arya M. Spry M. Wakamatsu K. Igras V. Kunisada T. Granter S.R. Nishimura E.K. et al.Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning.Nature. 2006; 443: 340-344Crossref PubMed Scopus (250) Google Scholar). Although RNA upregulation could occur through a variety of mechanisms, we examined the proximal 1 kb promoter region of the POMC gene to search for consensus transcription-factor-binding elements that are conserved between human, rat, and mouse. Among the various consensus elements found, one was particularly noteworthy due to its known regulation by UV: p53. We therefore examined primary human keratinocytes and the mouse keratinocyte line PAM212 for both POMC and p53 levels following UV, as shown in Figure 1. A 100 J/m2 UVB dose was administered in this experiment (see Experimental Procedures). This dose is equivalent to the standard erythema dose (SED; Diffey et al., 1997Diffey B.L. Jansen C.T. Urbach F. Wulf H.C. The standard erythema dose: a new photobiological concept.Photodermatol. Photoimmunol. Photomed. 1997; 13: 64-66Crossref PubMed Scopus (150) Google Scholar, CIE Standard, 1998CIE StandardErythema reference action spectrum and standard erythema dose. Commission Internationale de I'Eclairage, Vienna1998Google Scholar), which is commonly used as a measure of sunlight. As a point of reference, the ambient exposure on a clear summer day in Europe is approximately 30–40 SED. Also, an exposure dose of 4 SED would be expected to produce moderate erythema on unacclimated white skin but minimal or no erythema on previously exposed (tanned) skin. UV markedly induced expression of POMC mRNA and protein by 6 hr, and p53 induction was already maximal by 3 hr, which is consistent with its known stabilization by UV (Figures 1A and 1B). At 24 hr the levels of POMC protein were lower relative to those found after 6 hr in keratinocytes (human as well as mouse), probably as a result of the proteolytic processing and secretion by keratinocytes (Schauer et al., 1994Schauer E. Trautinger F. Kock A. Schwarz A. Bhardwaj R. Simon M. Ansel J.C. Schwarz T. Luger T.A. Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes.J. Clin. Invest. 1994; 93: 2258-2262Crossref PubMed Scopus (310) Google Scholar, Chakraborty et al., 1996Chakraborty A.K. Funasaka Y. Slominski A. Ermak G. Hwang J. Pawelek J.M. Ichihashi M. Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture: regulation by ultraviolet B.Biochim. Biophys. Acta. 1996; 1313: 130-138Crossref PubMed Scopus (287) Google Scholar). ELISA analysis of the corresponding culture media demonstrated >30-fold induction of α-MSH secretion by keratinocytes after UV (Figure S2). To test whether POMC is a p53-responsive gene in keratinocytes, we introduced pcDNA-HA-p53 or empty vector into the PAM212 keratinocyte cell line, and we assessed POMC expression by a real-time quantitative RT-PCR assay and immunoblotting (Figure 1C). POMC expression was significantly induced in response to p53 at both mRNA and protein levels. The rapid induction of POMC following UV radiation of keratinocytes is consistent with the rapid, posttranslational stabilization that is responsible for p53 upregulation following UV (Kastan et al., 1991Kastan M.B. Onyekwere O. Sidransky D. Vogelstein B. Craig R.W. Participation of p53 protein in the cellular response to DNA damage.Cancer Res. 1991; 51: 6304-6311PubMed Google Scholar, Gottifredi et al., 2000Gottifredi V. Shieh S.Y. Prives C. Regulation of p53 after different forms of stress and at different cell cycle stages.Cold Spring Harb. Symp. Quant. Biol. 2000; 65: 483-488Crossref PubMed Scopus (18) Google Scholar, Vogelstein et al., 2000Vogelstein B. Lane D. Levine A.J. Surfing the p53 network.Nature. 2000; 408: 307-310Crossref PubMed Scopus (5530) Google Scholar). To test whether POMC induction by p53 correlates with other p53-mediated functions such as apoptosis, the PAM212 keratinocyte cell line was transfected with varying doses of pcDNA-HA-p53 and assessed for apoptotic cells (by flow cytometry) as well as POMC mRNA (by qPCR). p53 overexpression triggered both POMC expression and apoptosis, and there was no obvious difference in threshold for these two endpoints (Figure S3), though differences might exist in other settings, such as within skin or with specific genetic backgrounds. Examination of POMC mRNA stability was also undertaken (±UV), and its decay kinetics were measured in the presence of actinomycin D (Figure S1). No significant changes in POMC mRNA stability were observed with UV. To examine whether p53 is required for UV-mediated induction of POMC, we stably introduced a synthetic dominant-negative p53 allele (p53DD; Shaulian et al., 1992Shaulian E. Zauberman A. Ginsberg D. Oren M. Identification of a minimal transforming domain of p53: negative dominance through abrogation of sequence-specific DNA binding.Mol. Cell. Biol. 1992; 12: 5581-5592Crossref PubMed Scopus (321) Google Scholar) into the PAM212 keratinocyte line and into the human primary foreskin keratinocytes (HFK) “PAMDD” and “HFKDD.” As shown in Figures 2A and S4A, ectopic expression of p53DD was seen to abrogate induction of both mRNA and protein levels of POMC following UV. We also studied keratinocytes from wild-type and p53 null mice (littermates). p53 nullizygous keratinocytes exhibited no measurable POMC mRNA upregulation following UV irradiation (Figure 2B). Of note, western blotting demonstrated that basal POMC expression (prior to UV) was not significantly diminished in the absence of p53, which suggests that p53 is not globally required for POMC expression but is essential for the UV-responsive induction of POMC in keratinocytes. This finding is corroborated by the obvious fact that p53−/− C57Bl6 mice exhibit black fur. A potential p53-binding site was identified in the POMC 5′-flanking region ∼300 bp upstream of the transcription initiation site in humans, and a similar site was identified in the mouse promoter (Bargonetti et al., 1991Bargonetti J. Friedman P.N. Kern S.E. Vogelstein B. Prives C. Wild-type but not mutant p53 immunopurified proteins bind to sequences adjacent to the SV40 origin of replication.Cell. 1991; 65: 1083-1091Abstract Full Text PDF PubMed Scopus (278) Google Scholar, Kern et al., 1991Kern S.E. Kinzler K.W. Bruskin A. Jarosz D. Friedman P. Prives C. Vogelstein B. Identification of p53 as a sequence-specific DNA-binding protein.Science. 1991; 252: 1708-1711Crossref PubMed Scopus (915) Google Scholar). A series of luciferase reporters was tested for UV responsiveness after being transfected into PAM212 keratinocytes. As shown in Figures 3A and 3B, deletion mutants, as well as a site-specific mutation at the p53 consensus element, abrogated UV responsiveness of the POMC promoter. Furthermore, parallel transfections into PAM212 and PAM212/p53DD revealed that suppression of endogenous p53 is sufficient to abrogate the UV-induced reporter activity (Figure 3C). Classical electrophoretic mobility shift assay (EMSA) demonstrated a UV-induced DNA-binding activity that was supershifted by anti-p53 antibody and that had sequence specificity for the p53 consensus probe (but not the point mutant) in keratinocyte nuclear extracts (Figure 3D). To determine whether p53 occupies the endogenous POMC promoter in cells, we used chromatin immunoprecipitation (ChIP) from UV-irradiated versus unirradiated mouse keratinocytes (PAM212) or human primary keratinocytes. p53 binding to the POMC promoter was detected following UV, whereas no association was detected in unirradiated cells (Figure 3E). Controls included ChIP of the p53 response element in the p21 promoter, in the actin promoter, and in intronic sequences of the POMC gene (negative controls). The human p53 protein was also able to bind to the mouse POMC promoter (Figure S4B). These data suggest that p53 directly modulates transcriptional activity of the POMC promoter following UV. To assess whether the induction of POMC by UV (via p53) occurs in nonkeratinocytes, we exposed melanocytes, fibroblasts, and spleen cells to UV. All three lineages displayed reproducible POMC induction, but the magnitude of the effect was significantly greater in keratinocytes (16- to 25-fold in keratinocytes versus ∼3-fold in nonkeratinocytes; Figures S5A and S6). Using p53−/− primary melanocytes, we found that even the modest (∼3-fold) induction of POMC by UV in melanocytes appears to require p53 (Figure S5B). The degree of p53 induction by UV did not predictably correlate with POMC induction in other cell types (e.g., melanocytes or mouse primary spleen cells; Figures S5A and S6), which suggests tissue-specific differences in POMC promoter responsiveness to p53 following UV. To test the in vivo requirement of p53 for UV pigmentation, age-matched wild-type and p53 null C57Bl6 mice were subjected to UV; this was followed by an evaluation of their ears and tails, which are two locations that contain epidermal melanocytes (furry regions lack epidermal melanocytes; Nordlund et al., 1986Nordlund J.J. Collins C.E. Rheins L.A. Prostaglandin E2 and D2 but not MSH stimulate the proliferation of pigment cells in the pinnal epidermis of the DBA/2 mouse.J. Invest. Dermatol. 1986; 86: 433-437Crossref PubMed Scopus (100) Google Scholar). As shown in Figures 4A, S7A, and S7B, visible tanning of ears and tails was observed in wild-type but not in p53 null mice. Interestingly, baseline pigmentation was not appreciably different in fur of p53 wild-type versus that of null mice but was reproducibly slightly lighter in epidermal tail skin of p53 nulls (Figure S7A). Histologic analyses revealed absence of both POMC and melanin induction in UV-irradiated p53−/− skin (Figures 4B and 4C). POMC mRNA induction was also directly measured in skin of the same mice following UV radiation. As shown in Figure 4D, significant POMC mRNA induction was observed following UV but was absent in p53−/− mice. Aside from α-MSH, another proteolytic cleavage product of POMC is the opioid receptor ligand β-endorphin, which previously has been suggested to be a mediator of sun-seeking behavior in man (Wintzen et al., 1996Wintzen M. Yaar M. Burbach J.P. Gilchrest B.A. Proopiomelanocortin gene product regulation in keratinocytes.J. Invest. Dermatol. 1996; 106: 673-678Crossref PubMed Scopus (122) Google Scholar, Wintzen et al., 2001Wintzen M. de Winter S. Out-Luiting J.J. van Duinen S.G. Vermeer B.J. Presence of immunoreactive beta-endorphin in human skin.Exp. Dermatol. 2001; 10: 305-311Crossref PubMed Scopus (22) Google Scholar, Kaur et al., 2006Kaur M. Liguori A. Fleischer Jr., A.B. Feldman S.R. Plasma beta-endorphin levels in frequent and infrequent tanners before and after ultraviolet and non-ultraviolet stimuli.J. Am. Acad. Dermatol. 2006; 54: 919-920Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). As shown in Figure 4E, expression of β-endorphin, like that of α-MSH, was induced by UV in a p53-dependent manner. These data indicate that p53 is essential for in vivo POMC induction following UV and establish p53 as an integral molecule in the tanning response. To explore whether similar events occur in the UV response of human skin, discarded normal human skin specimens were exposed to UV and stained over a time course for p53, α-MSH peptide, and the melanocytic transcription factor MITF. Induction of MITF by α-MSH/MC1R/cAMP indicates activation of the pigmentation pathway (D'Orazio et al., 2006D'Orazio J.A. Nobuhisa T. Cui R. Arya M. Spry M. Wakamatsu K. Igras V. Kunisada T. Granter S.R. Nishimura E.K. et al.Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning.Nature. 2006; 443: 340-344Crossref PubMed Scopus (250) Google Scholar) and serves to identify melanocytes in the basal epidermis. As shown in Figure 5, p53 is rapidly induced in virtually every epidermal keratinocyte by 1 hr after UV exposure. α-MSH is expressed later (3–6 hr) and is also seen throughout the epidermal keratinocyte population. MITF is strongly induced at 6 hr and localizes to the melanocyte nuclei that are found in the basal epidermal population (Figure 5) as previously reported by King et al., 1999King R. Weilbaecher K.N. McGill G. Cooley E. Mihm M. Fisher D.E. Microphthalmia transcription factor. A sensitive and specific melanocyte marker for melanoma diagnosis.Am. J. Pathol. 1999; 155: 731-738Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar. These studies indicate a similar temporal induction of signaling components following UV irradiation of either mouse or human skin. The role of p53 in the UV-pigment response is notable because p53 protein may be stabilized by various non-UV stressors, which raises the possibility that it may participate in cutaneous pigmentation in a variety of non-UV-associated settings. To test this, PAM212 keratinocytes were treated with the topoisomerase inhibitor etoposide, and induction of p53 and POMC was measured. As shown in Figure 6A, both p53 and POMC were induced. A simple test of the possibility that p53 may participate in non-UV skin hyperpigmentation is found in the response to topical 5-fluoro-uracil (5-FU), a known inducer of p53 (Lowe et al., 1994Lowe S.W. Bodis S. McClatchey A. Remington L. Ruley H.E. Fisher D.E. Housman D.E. Jacks T. p53 status and the efficacy of cancer therapy in vivo.Science. 1994; 266: 807-810Crossref PubMed Scopus (1515) Google Scholar). This drug is used in multiple human dermatologic conditions and has been described to induce hyperpigmentation as a side effect in a fraction of patients (PDR staff, 2005PDR staffDermatology.in: Physicians' Desk Reference. Thomson PDR, Montvale, NJ2005: 3267Google Scholar). As shown in Figures 6B and 6C, chronic exposure to topical 5-FU induced hyperpigmentation in p53 wild-type but not p53−/−, mouse skin, which suggests that non-UV triggers of p53 may also induce pigmentation. This result is consistent with previous reports that DNA damage (or its repair) can stimulate tanning (Eller et al., 1994Eller M.S. Yaar M. Gilchrest B.A. DNA damage and melanogenesis.Nature. 1994; 372: 413-414Crossref PubMed Scopus (168) Google Scholar, Eller et al., 1996Eller M.S. Ostrom K. Gilchrest B.A. DNA damage enhances melanogenesis.Proc. Natl. Acad. Sci. USA. 1996; 93: 1087-1092Crossref PubMed Scopus (232) Google Scholar). Ionizing radiation is also well known for hyperpigmentation induction (as well as p53" @default.
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• W2109349283 date "2007-03-01" @default.
• W2109349283 modified "2023-10-18" @default.
• W2109349283 title "Central Role of p53 in the Suntan Response and Pathologic Hyperpigmentation" @default.
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• W2109349283 doi "https://doi.org/10.1016/j.cell.2006.12.045" @default.
• W2109349283 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/17350573" @default.
• W2109349283 hasPublicationYear "2007" @default.

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