[Frontiers in Bioscience S2, 11-17, January 1, 2010]
The shady side of sunlight: current understanding of the mechanisms underlying UV-induction of skin cancers
Alison Trappey1, Augusta Fernando1, Rajiv Gaur1, Madhwa Raj2, Allal Ouhtit1
1
TABLE OF CONTENTS
1. ABSTRACT
The incidence of skin cancer has been rising at an astonishing rate, particularly that of the deadliest skin cancer, melanoma. While the molecular mechanisms of sunlight ultraviolet radiation (UV)-induced non-melanoma skin cancer (NMSC) have been well documented, there is a major gap in our current knowledge of how UV initiates melanoma. However, the components of the retinoblastoma (Rb) pathway, the p53 and the p16 pathways are considered the major targets of UV-induced NMSC and melanoma, respectively. Our recent study has revealed that these two pathways coordinate the early responses to UV radiation in the skin. Here, we review the value of studies targeting these early events of skin carcinogenesis, with specific focus on the critical role of the components of the Rb pathway.
2. INTRODUCTION
Skin cancer is the most common human malignancy in United states. There are over 1 million cases of non melanoma skin cancer (NMSC) occurring each year, and the incidence of cutaneous malignant melanoma (CMM) is rising more rapidly than any other malignancy (1). The relevance of sunlight exposure to the skin cancer epidemic is well known. One of the major contributory factors in this epidemic is increased recreational sun exposure (2, 3). Some protection against sun exposure occurs when the skin tans and thickens, and those who sun-burn easily and tan poorly have the least degree of protection, increasing their risk of developing skin cancer. Increased awareness of the dangers of sun exposure has spurred an interest into how ultraviolet (UV) radiation in sunlight causes skin cancer. These concerns are amplified by increasing discussions on the depleting ozone layer. The world health organization (WHO) estimates that a 10% decrease of ozone level will result in an additional 300,000 NMSC and 4,500 CMM per year (4). The incidence of NMSC increases in proportion to sunlight exposure, as seen in the elderly and outdoor workers (5). Although epidemiological studies supported by laboratory models indicate a relationship between UV light and melanoma (1), our knowledge of the underlying mechanisms is poor (6). This review will discuss the recent findings on the relationship between UV and the molecular mechanisms of NMSC and CMM, with specific interest into the early responses to UV insult, involving the coordination of p16 and the p53 pathways.
2.1. Sunlight ultraviolet radiation
Sunlight is composed of a continuous spectrum of electromagnetic radiation, divided into 3 main wavelengths, including ultraviolet, visible, and infra red. Visible light has a wavelength of 400-700 nm, and UV light compromises the wavelengths just short of visible light, those from 200-400nm. UV light can be divided into UVA (320-400), UVB (280-320), and UVC (280-320). The ozone layer of earth's atmosphere effectively blocks UVC from being absorbed, but both UVA and UVB reach earth's surface in amounts sufficient to damage skin and eyes. Humans are predominantly exposed to UVA, which has been shown to cause skin cancer in animals when given over a long period of time (7-10). Despite its low carcinogenic effect, it plays an important role in skin aging and wrinkling (11). In contrast, UVB causes a plethora of adverse effects ranging from erythema, burns, immune suppression, increased photo aging, and eventually skin cancers (11).
2.2. DNA Damage in the skin
In properly functioning human epidermis, cells turn over about once a month. Stem cells in the basal layer undergo cell division, and the keratinocytes differentiate into squamous cells, producing keratin and other proteins. Eventually, the cells desquamate (12). In UV-induced skin carcinogenesis, cells lose the ability to control proliferation (11). When the DNA of epidermal cells absorbs photons, electron rearrangement leads to the formation of photoproducts at adjacent pyramidine sites (13). In normal cells, these photoproducts can be removed by the nucleotide excision repair mechanism mediated by p53 (14). Photo damage elevates p53 expression in the skin, thus blocking the cell cycle at G1-S phase. This allows repair of damage or apoptosis to eliminate cells with severely damaged DNA (15, 16). In a chronic UV scenario, DNA photoproducts can become carcinogenic and be passed on during replication as C to T or CC to TT mutations. These mutations are known as genetic fingerprints (17). Unfortunately, the p53 gene can itself be mutated by UV radiation resulting in uncontrolled cell proliferation and loss of apoptosis by DNA damaged cells (18). Xeroderma pigmentosum individuals, which have defective DNA repair machinery, extreme sun sensitivity and high incidence of skin cancer, provide evidence of the importance of DNA repair mechanisms (2). UV-induced DNA damage also effects immune surveillance in the skin. Normally, immune surveillance protects against the development of skin cancer. But, UV exposure depresses the function of the immune system leading to an environment that is more favorable to development and growth of tumors (3).
2.3. Non-melanoma skin cancer
NMSC, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common skin cancers. Over one million new cases of NMSC occur each year in the United States (5). Although mortality from NMSC is low, morbidity is high due to disfigurement and medical costs. It is estimated that treatment cost per year is over $500 million dollars (2). Unfortunately, the incidence of skin cancer is expected to increase emphasizing the importance of prevention and treatment efforts (11). Since 1985, BCC rates have increased by 35%. BCCs mostly occur in individuals at an age over 30, and they are most commonly manifest on sun-exposed areas such as the face, the head, and the neck. BCCs do not metastasize, but must be treated as soon as possible to prevent invasive growth. The most frequent treatment is surgery to remove the primary tumor, but chemotherapy, cryotherapy, radiation, or topical treatments may also be used (4, 18). According to the WHO, SCC rates have increased by as much as 133% since 1985. Although less common than BCC, squamous cell carcinoma (SCC) carries a risk for metastasis. Most SCCs develop from precursor lesions such as actinic keratosis (AK) and are diagnosed on sun-exposed areas of the head, neck, and dorsal hands. Generally, SCC can metastasize to regional lymph nodes and are usually detected 1-3 years after the initial diagnosis. Therapy for SCC is similar to that for BCC mentioned above, with surgery again being the most common treatment (4, 18).
2.4. Melanoma
Melanoma, the deadliest skin cancer, is the most common form of cancer for young adults 25-29 years old. More than 116,500 new cases of melanoma will be diagnosed in the United States in 2008. In the United States, the lifetime risk in developing melanoma is 1 in 75, and the five year survival rate for metastatic melanoma is only 14% (18). Although melanoma is much less common than NMSC, it affects younger population and mortality rates are high for thicker lesion (19). CMM affects pigmented cells found in the epidermal layer of skin known as melanocytes (20). Evidence indicates that CMM risk factors are both genetic and environmental. CMM incidence is rapidly increasing and shows resistance to currently available therapies. Understanding the mechanisms involved in CMM development is therefore needed (21).
3. MOLECULAR MECHANISMS OF UV-INDUCED NON-MELANOMA SKIN CANCERS
Our previous studies have extensively contributed to a better understanding of the molecular and cellular mechanisms implicated in the early responses to UV radiation during photocarcinogenesis (11, 12, 15, 22-31). The components of the p53 pathway emerge as the major targets of UV-induced NMSC as described in figure
1. Chronic UV radiation mutates the sensor of DNA damage, p53, at specific sites which are essential to p53 function in regulating cell proliferation and apoptosis (12, 15, 23-27).
3.1. The components of the p53 pathway
Human p53 gene is highly conserved, and is localized on chromosome 17p13. It contains 11 exons encoding a 53,000 molecular weight protein containing 393 amino acids (32) with a number of well-characterized functional domains. Activation of p53 by phosphorylation, dephosphorylation, and acetylation yields a potent sequence specific DNA-binding transcription factor important in modulating multiple cellular functions. These functions include gene transcription, DNA synthesis and repair, cell cycle control, senescence, and apoptosis (33-37). As described in figure 1, UV-irradiation activates the sensor of DNA damage, p53, which induces its downstream target genes including the cell cycle inhibitor, p21 which halts cell division via Rb to allow the repair of DNA damage. If the damage is severe, apoptosis is triggered through p53-dependent Bax/Bcl-2 pathway and/or via Fas/Fas-ligand pathway to eliminate keratinocytes carrying Uv-damaged DNA. Dysfunction of these mechanisms occurs when p53 is mutated. These findings indicate the importance of the components of p53 pathway in the onset of UV-induced NMSC. Defining all the players that function as upstream regulators and downstream mediators of the p53 signaling pathway remains a significant challenge.
The p53 gene can be mutated by UV irradiation resulting in uncontrolled cell proliferation and loss of apoptosis of DNA damaged cells. Mutations of p53 are found in about 56% of BCC (11) and >90% of SCC (16). The importance of p53 inactivation in NMSC is further demonstrated by the observation that homozygous and heterozygous p53 knockout mice develop skin tumors much earlier than wild-type mice upon exposure to UV light (38). In SCC, following UV exposure, p53 mutations accumulate with clonal expansion of affected keratinocytes and the formation of premalignant actinic keratosis. These premalignant lesions can regress or progress to invasive SCC depending on environmental factors and the status of the immune system. p53 also plays an important role in BCC formation, but additional mechanisms besides p53 is known.
3.2. Deregulation of Apoptosis by UV
Our previous studies have significantly contributed to our understanding of the mechanisms by which UV radiation induces NMSC. This complex process involves both mutagenic and immunosuppressive pathways that are most likely triggered by UV-induced DNA damage (11). As described above, excessive damage induced by UV-irradiation leads to apoptosis (39). However, following chronic UV exposure, photoproducts can persist and become carcinogenic mutations, particularly the UV-signature mutations in the p53 gene C to T or CC to TT (16). Nine hotspot p53 mutations were identified in human skin tumors at codons 152, 177, 179, 196, 245, 247/248, 273, 277 and 281/282 (17, 40). Several lines of evidence indicate that these mutations play a critical role in the initiation process of skin photocarcinogenesis (17). Certain mutations can confer oncogenic function to p53 leading to deregulation of its p53-dependent apoptosis function. With sustained exposure to UVB, cells with p53 mutations clonally expand to form mutated p53 clones in the epidermis (13, 41). Thus, deregulation of UV-induced apoptosis might be the initiating event in photocarcinogenesis (24, 26).
3.3. Other key genes in NMSC
Although p53 is an essential early event in BCC, some of these tumors originate through UV light mediated mutations of the genes implicated in the hedgehog signaling pathway, including ptch and Smo (18). These genes are essential for the maintainance of cell growth and differentiation via the downstream Gli genes. Mutations inactivating ptch gene and gain of function mutations in Smo have been described in BCCs associated with solar UV exposure (42). These mutations lead to dysfunction of the hedgehog signaling pathway generating abnormal cell proliferation, and contributing to the onset of BCC tumors.
4. MOLECULAR MECHANISMS OF UV-INDUCED MELANOMA
Accumulating evidence shows that the risks of CMM include both genetic and environmental factors (21). Cytogenetic tudies have identified two genes linked to melanoma, CDKN2A (INK4a/ARF) located at 9p21 locus and CDK4 located at 12q13 locus. In human melanoma, the most common genetic lesion is loss of INK4a/ARF locus along with the activation of the BRAF mutation (43). CDKN2A (INK4a/ARF) locus encodes for two distinct tumor suppressor proteins: p16INKa, the inhibitor of kinase 4A, and p14ARF (44-47). Although the functional relationship between genes and sunlight pathogenesis is not well understood, the development of animal models has, however, linked UV to melanoma development (48, 49). These models have identified the p16/Rb pathway as the major target of UV-induced melanomagenesis.
4.1. 1. UV and P16/Rb pathway
In a melanoma model driven by H-RAS activation and loss of p19ARF function, UV radiation accelerated melanoma genesis, which was accompanied by amplification of cyclin-dependent kinase (cdk) 6, whereas none of the melanomas arising in the absence of UV treatment possessed cdk6 amplification (50). In addition, UV-induced melanomas showed an inverse relationship between cdk6 amplification and p16INK4a loss, which is consistent with the effects of UV radiation on p16/Rb pathway. In duction of p16INK4a regulates the cell cycle by specifically inhibiting CDK4/6. leading to formation of Rb-E2F complex preventing E2F-responsive genes necessary for entry into S phase of the cell cycle (51). Rb protein is in its non-phosphorylated or active form, EF2 is not activated, and replication is halted. If p16INK4a is inactivated by a missense mutation, deletion, or methylation, the Rb protein is no longer maintained in its active form and cell replication goes unchecked leading to deregulation of the mechanisms controlling cell proliferation (30).
The CDK4 gene, coding for a protein that binds to p16, has also been identified as a melanoma susceptibility gene (52). A CDK4 mutation has been found in melanoma prone families (53, 54) and produces a mutated protein with oncogenec activity; this protein interferes with the binding of the CDK4 protein to p16, preventing inhibition of its enzymatic activity, thereby leading to unchecked cellular division (55) (59 I think this is 49 and I am adding reference 49).
4.2. UV and P53/Rb pathway
The effect of UV radiation on p53 expression in the skin has been well documented (1-3, 5-15, 29). In a mouse model, p53 expression increased 12 hours after UV exposure. Following this, p21 protein increased arresting the cell cycle and permitting repair of UV DNA damage in the skin. Apoptosis is induced in the skin through p53 dependant or independent pathways following severe damage (15). Although the role of the components of the p53 pathway is well established in NMSC development, its relationship with melanomagenesis is unclear. However, our recent study revealed that the components of the p53 pathway might play an essential role in regulating cell proliferation and apoptosis, particularly in response to higher doses of UV radiation (32). Moreover, the cell cycle inhibitor p14ARF regulates HMD2, an E3 ubiquitin ligase controling p53 degradation and stability (56). p14ARF prevents the interaction between p53 and HDM2 resulting in the accumulation of p53 protein, which in turn induces p21 to arrest cell cycle as described above. These events are disrupted when ARF is mutated and loses its tumor suppression function, potentially contributing to melanoma development (30). Thus, the p16/Rb and the components of the p53 pathway play a major role in coordinating the early responses to UV radiation in the skin (32).
5. CONCLUSION
The evil side of sunlight is evidenced by the alarming rise in the incidence of skin cancer over the past few decades. Despite the slow progress in elucidating the mechanisms by which UV induces melanoma, findings from our own work and others have significantly impacted our current knowledge of these mechanisms. Sunlight UV radiation appears to target the two tumor suppressor genes, p53 and p16, the main backbone regulators of the Rb pathway, at the early stages of photocarcinogenesis. UV seems to favor the p16/Rb pathway in melanoma, while it affects the ARF-independent p53 pathway in NMSC. As more pieces of the puzzle continue to fit together to help guide the development of targeted therapies for skin cancers, protecting our skin from sunlight can prevent its evil side.
6. AKNOWLEDGEMENT
This work was supported by the Louisiana Cancer Research Consortium of New Orleans
7. REFERENCES
1. Benjamin CL, Melnikova VO, and Ananthaswamy HN: Models and mechanisms in malignant melanoma. Mol Carcinog 46, 671-678 (2007)
doi:10.1002/mc.20353
2. Strom S: Epidemiology of basal and squamous cellcarcinomas of the skin. In: Basal and squamous cell skincancers of the head and neck. Williams and Wilkins Baltimore (1996)
3. Kanjilal S and Ananthaswamy HN: Molecular of skin carcinomas. In: Basal and squamous cell cancers of the head and neck. Williams and Wilkins Baltimore (1996)
4. Erb P, Ji J, Wernli M, Kump E, Glaser A and Buchner SA: Role of apoptosis in basal cell and squamous cell carcinoma formation. Immunol Lett 100, 68-72 (2005)
doi:10.1016/j.imlet.2005.06.008
5. Gloster HM Jr, and Brodland DG: The epidemiology of skin cancer. Dermatol Surg 22, 217-226 (1996)
doi:10.1016/1076-0512(95)00570-6
6. Li W, Sanki A, Karim RZ, Thompson JF, Soon Lee C, Zhuang L, McCarthy SW and Scolyer RA: The role of cell cycle regulatory proteins in the pathogenesis of melanoma. Pathology 38, 287-301 (2006)
doi:10.1080/00313020600817951
7. Zigman S, Fowler E and Krause AL: Black light induction of skin tumors in mice. J Invest Dermatol 67, 723-725 (1976)
doi:10.1111/1523-1747.ep12598612
8. Strickland PT: Photocarcinogenesis by near-ultraviolet (UVA) radiation in Sencar mice. J Invest Dermatol 87, 272-275 (1986)
doi:10.1111/1523-1747.ep12696669
9. Setlow RB, Woodhead AD and Grist E: Animal model for ultraviolet radiation-induced melanoma: platyfish-swordtail hybrid. Proc Natl Acad Sci U S A 86, 8922-8926 (1989)
doi:10.1073/pnas.86.22.8922
10. Setlow RB, Grist E, Thompson K and Woodhead AD: Wavelengths effective in induction of malignant melanoma. Proc Natl Acad Sci U S A 90, 6666-6670 (1993)
doi:10.1073/pnas.90.14.6666
11. Soehnge H, Ouhtit A and Ananthaswamy HN: Mechanisms of induction of skin cancer by UV radiation. Front Biosci 2, d538-551 (1997)
12. Ouhtit A and Ananthaswamy HN: A Model for UV-Induction of Skin Cancer. J Biomed Biotechnol 1, 5-6 (2001)
doi:10.1155/S1110724301000031
13. Brash DE: UV mutagenic photoproducts in Escherichia coli and human cells: a molecular genetics perspective on human skin cancer. Photochem Photobiol 48, 59-66 (1988)
14. Ford JM and Hanawalt PC: Expression of wild-type p53 is required for efficient global genomic nucleotide excision repair in UV-irradiated human fibroblasts. J Biol Chem 272, 28073-28080 (1997)
doi:10.1074/jbc.272.44.28073
15. Ouhtit A, Muller HK, Davis DW, Ullrich SE, McConkey D and Ananthaswamy HN: Temporal events in skin injury and the early adaptive responses in ultraviolet-irradiated mouse skin. Am J Pathol 156, 201-207 (2000)
16. Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, Remington L, Jacks T and Brash DE: Sunburn and p53 in the onset of skin cancer. Nature 372, 773-776 (1994)
doi:10.1038/372773a0
17. Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, Halperin AJ and Ponten J: A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A 88, 10124-10128 (1991)
doi:10.1073/pnas.88.22.10124
18. Erb P, Ji J, Kump E, Miegla A and Wernli M: Apoptosis and pathogenesis of melanoma and nonmelanoma skin cancer. Sunlight, Vitamin D and Skin Cancer. Adv Exp Med Biol 624, 283-295 (2008)
doi:10.1007/978-0-387-77574-6_22
19. Forrest APM, Carter DC and MacLeod IB: Principles and Practice of Surgery. UK: Churchill Livingstone Edinburgh (1995)
20. Welch DR and Goldberg SF: Molecular mechanisms controlling human melanoma progression and metastasis. Pathobiology 65, 311-330 (1997)
doi:10.1159/000164143
21. Bressac-de-Paillerets B, Avril MF, Chompret A and Demenais F: Genetic and environmental factors in cutaneous malignant melanoma. Biochimie 84, 67-74 (2002)
doi:10.1016/S0300-9084(01)01360-8
22. Ouhtit A, Ueda M, Nakazawa H, Ichihashi M, Dumaz N, Sarasin A and Yamasaki H: Quantitative detection of ultraviolet-specific p53 mutations in normal skin from Japanese patients. Cancer Epidemiol Biomarkers Prev 6, 433-438 (1997)
23. Ouhtit A, Nakazawa H, Armstrong BK, Kricker A, Tan E, Yamasaki H and English DR: UV-radiation-specific p53 mutation frequency in normal skin as a predictor of risk of basal cell carcinoma. J Natl Cancer Inst 90, 523-531 (1998)
doi:10.1093/jnci/90.7.523
24. Hill LL, Ouhtit A, Loughlin SM, Kripke ML, Ananthaswamy HN and Owen-Schaub LB: Fas ligand: a sensor for DNA damage critical in skin cancer etiology. Science 285, 898-900 (1999)
doi:10.1126/science.285.5429.898
25. Ananthaswamy HN, Ouhtit A, Evans RL, Gorny A, Khaskina P, Sands AT and Conti CJ: Persistence of p53 mutations and resistance of keratinocytes to apoptosis are associated with the increased susceptibility of mice lacking the XPC gene to UV carcinogenesis. Oncogene 18, 7395-7398 (1999)
doi:10.1038/sj.onc.1203147
26. Ouhtit A, GornyA, Muller HK, Hill LL, Owen-Schaub L and Ananthaswamy HN: Loss of Fas-ligand expression in mouse keratinocytes during UV carcinogenesis. Am J Pathol 157, 1975-1981 (2000)
27. Ouhtit A, Muller HK, Gorny A and Ananthaswamy HN: UVB-induced experimental carcinogenesis: dysregulation of apoptosis and p53 signalling pathway. Redox Rep 5, 128-129 (2000)
doi:10.1179/135100000101535447
28. Jiang W, Ananthaswamy HN, Muller HK, Ouhtit A, Bolshakov S, Ullrich SE, El-Naggar AK and Kripke ML: UV irradiation augments lymphoid malignancies in mice with one functional copy of wild-type p53. Proc Natl Acad Sci U S A 98, 9790-9795 (2001)
doi:10.1073/pnas.171066498
29. Gervin CM, McCulla A, Williams M and Ouhtit A: Dysfunction of p53 in photocarcinogenesis. Front Biosci 8, s715-717 (2003)
doi:10.2741/1136
30. Williams M and Ouhtit A: Towards a Better Understanding of the Molecular Mechanisms Involved in Sunlight-Induced Melanoma. J Biomed Biotechnol 2005, 57-61 (2005)
doi:10.1155/JBB.2005.57
31. Abd Elmageed ZY, Gaur RL, Williams M, Abdraboh ME, Rao PN, Raj MH, Ismail FM and Ouhtit A: Characterization of coordinated immediate responses by p16INK4A and p53 pathways in UVB-irradiated human skin cells. J Invest Dermatol 129, 175-183 (2009)
doi:10.1038/jid.2008.208
32. Harlow E, Williamson NM, Ralston R, Helfman DM and Adams TE: Molecular cloning and in vitro expression of a cDNA clone for human cellular tumor antigen p53. Mol Cell Biol 5, 1601-1610 (1985)
33. Resnick-Silverman L, Manfredi JJ: Gene-specific mechanisms of p53 transcriptional control and prospects for cancer therapy. J Cell Biochem. 99, 679-89 (2006)
doi:10.1002/jcb.20925
34. Hartwell LH and Weinert TA: Checkpoints: controls that ensure the order of cell cycle events. Science 246, 629-634 (1989)
doi:10.1126/science.2683079
35. Lane DP: Cancer. p53, guardian of the genome. Nature 358, 15-16(1992)
doi:10.1038/358015a0
36. Hao M, Lowy AM, Kapoor M, Deffie A, Liu G and G Lozano: Mutation of phosphoserine 389 affects p53 function in vivo. J Biol Chem 271, 29380-29385 (1996)
doi:10.1074/jbc.271.46.29380
37. Gu W and Roeder RG: Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595-606 (1997)
doi:10.1016/S0092-8674(00)80521-8
38. Jiang W, Ananthaswamy HN, Muller HK and Kripke ML: p53 protects against skin cancer induction by UV-B radiation. Oncogene 18, 4247-4253 (1999)
doi:10.1038/sj.onc.1202789
39. Naik E, Michalak EM, Villunger A, Adams JM and Strasser A: Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa. J Cell Biol 176, 415-424 (2007)
doi:10.1083/jcb.200608070
40. Daya-Grosjean L, Dumaz N and Sarasin A: The specificity of p53 mutation spectra in sunlight induced human cancers. J Photochem Photobiol 28, 115-124 (1995)
doi:10.1016/1011-1344(95)07130-T
41. Zhang W, Remenyik E, Zelterman D, Brash DE and Wikonkal NM: Escaping the stem cell compartment: sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations. Proc Natl Acad Sci U S A 98, 13948-13953 (2001)
doi:10.1073/pnas.241353198
42. Daya-Grosjean L and Couve-Privat S: Sonic hedgehog signaling in basal cell carcinomas. Cancer Lett 225, 181-192 (2005)
doi:10.1016/j.canlet.2004.10.003
43. Castellano M and Parmiani G: Genes involved in melanoma: an overview of INK4a and other loci. Melanoma Res 9, 421-432 (1999)
44. Gilchrest BA, Eller MS, Geller AC and Yaar M: The pathogenesis of melanoma induced by ultraviolet radiation. N Engl J Med 340, 1341-1348 (1999)
doi:10.1056/NEJM199904293401707
45. Larsen CJ: p16INK4a: a gene with a dual capacity to encode unrelated proteins that inhibit cell cycle progression. Oncogene 12, 2041-2044 (1996)
46. Quelle DE, Zindy F, Ashmun RA and Sherr CJ: Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83, 993-1000 (1995)
doi:10.1016/0092-8674(95)90214-7
47. Sharpless NE and DePinho RA: The INK4A/ARF locus and its two gene products. Curr Opin Genet Dev 9, 22-30(1999)
doi:10.1016/S0959-437X(99)80004-5
48. Noonan FP, Recio JA, Takayama H, Duray P, Anver MR, Rush WL, De Fabo EC and Merlino G: Neonatal sunburn and melanoma in mice. Nature 413, 271-272 (2001)
doi:10.1038/35095108
49. Jhappan C, Noonan FP and Merlino G: Ultraviolet radiation and cutaneous malignant melanoma. Oncogene 22, 3099-3112 (2003)
doi:10.1038/sj.onc.1206450
50. Kannan K, Sharpless NE, Xu J, O'Hagan RC, Bosenberg M and Chin L: Components of the Rb pathway are critical targets of UV mutagenesis in a murine melanoma model. Proc Natl Acad Sci U S A 100, 1221-1225 (2003)
doi:10.1073/pnas.0336397100
51. Shirodkar S, Ewen M, DeCaprio JA, Morgan J, Livingston DM and Chittenden T: The transcription factor E2F interacts with the retinoblastoma product and a p107-cyclin A complex in a cell cycle-regulated manner. Cell 68, 157-166 (1992)
doi:10.1016/0092-8674(92)90214-W
52. Ghiorzo P and Scarra GB: Genetics of melanoma susceptibility. Forum (Genova) 13, 114-22 (2003)
53. Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N and Dracopoli NC: Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 12, 97-99 (1996)
doi:10.1038/ng0196-97
54. Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, Stoppa-Lyonnet D, Benard J and Bressac-de Paillerets B: Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet 7, 209-216 (1998)
doi:10.1093/hmg/7.2.209
55. Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmann-Hieb E, De Plaen E, Hankeln T, Meyer zum Buschenfelde KH and Beach D: A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269, 1281-1284 (1995)
doi:10.1126/science.7652577
56. Honda R and Yasuda H: Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. Embo J 18, 22-27 (1999)
doi:10.1093/emboj/18.1.22
Abbreviations: Rb: Retinoblastoma, NMSC: non melanoma skin cancer, CMM: cutaneous malignant melanoma, UV: ultraviolet WHO: world health organization, BCC: basal cell carcinoma, SCC: squamous cell carcinoma, AK: actinic keratosis, Ptch: Patched gene, Smo: smoothened gene, p16INKa: the inhibitor of kinase 4A, CDK4: cyclin dependenet kinase 4, HMD2: human double minute 2 gene.
Key Words: Sunlight Ultraviolet Radiation, Skin Cancer, p53, p16, Rb, Cell Proliferation, Apoptosis, Review
Send correspondence to: Allal Ouhtit, Pathology, Stanley S Scott Cancer Center, LSU Health Sciences Center, CSRB, 533 Bolivar Street, New Orleans, LA, U.S.A., 70112, Tel: 504-568-2896, Fax: 504-568-2932, E-mail:aouhti@lsuhsc.edu