Abstract
Inactivation of the INK4a/ARF (or CDKN2a) locus is a common and critical genetic event in the development of human and mouse melanoma. This locus engages the Rb and p53 tumor suppressor pathways through its capacity to encode two distinct gene products, p16INK4a and p14ARF. This review highlights the body of evidence supporting a role for both p16INK4a and p14ARF in the suppression of melanoma, and speculates as to why this locus is preferentially targeted in this tumor type. In addition, the potential importance of these two pathways in mediating UV-induced melanoma genesis will be addressed via genetic and molecular evidence in the mouse.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D and Barrett JC . (1996). Proc. Natl. Acad. Sci. USA, 93, 13742–13747.
Alevizopoulos K, Vlach J, Hennecke S and Amati B . (1997). EMBO J., 16, 5322–5333.
Atillasoy ES, Seykora JT, Soballe PW, Elenitsas R, Nesbit M, Elder DE, Montone KT, Sauter E and Herlyn M . (1998). Am. J. Pathol., 152, 1179–1186.
Bardeesy N, Bastian BC, Hezel A, Pinkel D, DePinho RA and Chin L . (2001). Mol. Cell. Biol., 21, 2144–2153.
Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL and Vousden KH . (1998). Nature, 395, 124–125.
Berking C, Takemoto R, Binder RL, Hartman SM, Ruiter DJ, Gallagher PM, Lessin SR and Herlyn M . (2002). Carcinogenesis, 23, 181–187.
Berns K, Hijmans EM and Bernards R . (1997). Oncogene, 15, 1347–1356.
Bouchard C, Thieke K, Maier A, Saffrich R, Hanley-Hyde J, Ansorge W, Reed S, Sicinski P, Bartek J and Eilers M . (1999). EMBO J., 18, 5321–5333.
Chin L, Pomerantz J, Polsky D, Jacobson M, Cohen C, Cordon-Cardo C, Horner II JW and DePinho RA . (1997). Genes Dev., 11, 2822–2834.
Daksis JI, Lu RY, Facchini LM, Marhin WW and Penn LJ . (1994). Oncogene, 9, 3635–3645.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR and Futreal PA . (2002). Nature, 417, 949–954.
de Stanchina E, McCurrach ME, Zindy F, Shieh SY, Ferbeyre G, Samuelson AV, Prives C, Roussel MF, Sherr CJ and Lowe SW . (1998). Genes Dev., 12, 2434–2442.
Donawho CK and Kripke ML . (1991). Cancer Res., 51, 4176–4181.
Duro D, Bernard O, Della Valle V, Berger R and Larsen CJ . (1995). Oncogene, 11, 21–29.
Fahraeus R and Lane DP . (1999). EMBO J., 18, 2106–2118.
Flores JF, Walker GJ, Glendening JM, Haluska FG, Castresana JS, Rubio MP, Pastorfide GC, Boyer LA, Kao WH, Bulyk ML, Barnhill RL, Hayward NK, Housman DE and Fountain JW . (1996). Cancer Res., 56, 5023–5032.
Galaktionov K, Chen X and Beach D . (1996). Nature, 382, 511–517.
Gilchrest BA, Eller MS, Geller AC and Yaar M . (1999). N. Engl. J. Med., 340, 1341–1348.
Glendening JM, Flores JF, Walker GJ, Stone S, Albino AP and Fountain JW . (1995). Cancer Res., 55, 5531–5535.
Harrison SL, MacLennan R, Speare R and Wronski I . (1994). Lancet, 344, 1529–1532.
Herlyn M and Satyamoorthy K . (1996). Am. J. Pathol., 149, 739–744.
Hermeking H, Rago C, Schuhmacher M, Li Q, Barrett JF, Obaya AJ, O'Connell BC, Mateyak MK, Tam W, Kohlhuber F, Dang CV, Sedivy JM, Eick D, Vogelstein B and Kinzler KW . (2000). Proc. Natl. Acad. Sci. USA, 97, 2229–2234.
Holland EA, Beaton SC, Becker TM, Grulet OM, Peters BA, Rizos H, Kefford RF and Mann GJ . (1995). Oncogene, 11, 2289–2294.
Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, Clark Jr WH, Tucker MA and Dracopoli NC . (1994). Nat. Genet., 8, 15–21.
Jamal S and Schneider RJ . (2002). J. Clin. Invest., 110, 443–452.
Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day III RS, Johnson BE and Skolnick MH . (1994a). Science, 264, 436–440.
Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, Hussey C, Tran T, Miki Y and Weaver-Feldhaus J et al. (1994b). Nat. Genet., 8, 23–26.
Kamijo T, Bodner S, van de Kamp E, Randle DH and Sherr CJ . (1999). Cancer Res., 59, 2217–2222.
Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF and Sherr CJ . (1998). Proc. Natl. Acad. Sci. USA, 95, 8292–8297.
Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G and Sherr CJ . (1997). Cell, 91, 649–659.
Kannan K, Sharpless NE, Xu J, O'Hagan RC, Bosenberg M and Chin L . (2003). Proc. Natl. Acad. Sci. USA, 100, 1221–1225.
Krimpenfort P, Quon KC, Mooi WJ, Loonstra A and Berns A . (2001). Nature, 413, 83–86.
Linggi B, Muller-Tidow C, van de Locht L, Hu M, Nip J, Serve H, Berdel WE, van der Reijden B, Quelle DE, Rowley JD, Cleveland J, Jansen JH, Pandolfi PP and Hiebert SW . (2002). Nat. Med., 8, 743–750.
Liu L, Lassam NJ, Slingerland JM, Bailey D, Cole D, Jenkins R and Hogg D . (1995). Oncogene, 11, 405–412.
Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH and Hannon GJ . (1999). Genes Dev., 13, 2207–2217.
Mao L, Merlo A, Bedi G, Shapiro GI, Edwards CD, Rollins BJ and Sidransky D . (1995). Cancer Res., 55, 2995–2997.
Nairn RS, Kazianis S, McEntire BB, Della Coletta L, Walter RB and Morizot DC . (1996). Proc. Natl. Acad. Sci. USA, 93, 13042–13047.
Noonan FP, Recio JA, Takayama H, Duray P, Anver MR, Rush WL, De Fabo EC and Merlino G . (2001). Nature, 413, 271–272.
O'Hagan RC, Ohh M, David G, de Alboran IM, Alt FW, Kaelin WG and DePinho RA . (2000). Genes Dev., 14, 2185–2191.
Pavey S, Conroy S, Russell T and Gabrielli B . (1999). Cancer Res., 59, 4185–4189.
Pavey S, Russell T and Gabrielli B . (2001). Oncogene, 20, 6103–6110.
Piepkorn M . (2000). J. Am. Acad. Dermatol., 42, 741–745.
Pollock PM, Pearson JV and Hayward NK . (1996). Genes Chromosomes Cancer, 15, 77–88.
Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C and DePinho RA . (1998). Cell, 92, 713–723.
Quelle DE, Zindy F, Ashmun RA and Sherr CJ . (1995). Cell, 83, 993–1000.
Radfar A, Unnikrishnan I, Lee HW, DePinho RA and Rosenberg N . (1998). Proc. Natl. Acad. Sci. USA, 95, 13194–13199.
Randerson-Moor JA, Harland M, Williams S, Cuthbert-Heavens D, Sheridan E, Aveyard J, Sibley K, Whitaker L, Knowles M, Newton Bishop J and Bishop DT . (2001). Hum. Mol. Genet., 10, 55–62.
Reznikoff CA, Yeager TR, Belair CD, Savelieva E, Puthenveettil JA and Stadler WM . (1996). Cancer Res., 56, 2886–2890.
Rizos H, Puig S, Badenas C, Malvehy J, Darmanian AP, Jimenez L, Mila M and Kefford RF . (2001). Oncogene, 20, 5543–5547.
Robles SJ and Adami GR . (1998). Oncogene, 16, 1113–1123.
Rocco JW and Sidransky D . (2001). Exp. Cell Res., 264, 42–55.
Ruas M and Peters G . (1998). Biochim. Biophys. Acta, 1378, F115–F177.
Santoni-Rugiu E, Falck J, Mailand N, Bartek J and Lukas J . (2000). Mol. Cell Biol., 20, 3497–3509.
Schmid M, Malicki D, Nobori T, Rosenbach MD, Campbell K, Carson DA and Carrera CJ . (1998). Oncogene, 17, 2669–2675.
Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM and Lowe SW . (2002). Cell, 109, 335–346.
Serrano M, Hannon GJ and Beach D . (1993). Nature, 366, 704–707.
Serrano M, Lin AW, McCurrach ME, Beach D and Lowe SW . (1997). Cell, 88, 593–602.
Shapiro GI, Edwards CD, Ewen ME and Rollins BJ . (1998). Mol. Cell Biol., 18, 378–387.
Sharpless NE, Alson S, Chan S, Silver DP, Castrillon DH and DePinho RA . (2002). Cancer Res., 62, 2761–2765.
Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW and DePinho RA . (2001). Nature, 413, 86–91.
Sharpless NE and DePinho RA . (1999). Curr. Opin. Genet Dev., 9, 22–30.
Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C and Lowe SW . (2001). Nature, 409, 207–211.
Sotillo R, Garcia JF, Ortega S, Martin J, Dubus P, Barbacid M and Malumbres M . (2001). Proc. Natl. Acad. Sci. USA, 98, 13312–13317.
Stone S, Jiang P, Dayananth P, Tavtigian SV, Katcher H, Parry D, Peters G and Kamb A . (1995). Cancer Res., 55, 2988–2994.
Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH and Peters G . (1998). EMBO J., 17, 5001–5014.
Tang L, Li G, Tron VA, Trotter MJ and Ho VC . (1999). Melanoma Res., 9, 148–154.
Vlach J, Hennecke S, Alevizopoulos K, Conti D and Amati B . (1996). EMBO J., 15, 6595–6604.
Walker GJ, Flores JF, Glendening JM, Lin AH, Markl ID and Fountain JW . (1998). Genes Chromosomes Cancer, 22, 157–163.
Walker GJ, Hussussian CJ, Flores JF, Glendening JM, Haluska FG, Dracopoli NC, Hayward NK and Fountain JW . (1995). Hum. Mol. Genet., 4, 1845–1852.
Wieser RJ, Faust D, Dietrich C and Oesch F . (1999). Oncogene, 18, 277–281.
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 . (1995). Science, 269, 1281–1284.
Zanetti R, Franceschi S, Rosso S, Colonna S and Bidoli E . (1992). Eur. J. Cancer, 28A, 1172–1176.
Zhang S, Ramsay ES and Mock BA . (1998a). Proc. Natl. Acad. Sci. USA, 95, 2429–2434.
Zhang Y, Xiong Y and Yarbrough WG . (1998b). Cell, 92, 725–734.
Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ and Roussel MF . (1998). Genes Dev., 12, 2424–2433.
Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N and Dracopoli NC . (1996). Nat. Genet., 12, 97–99.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sharpless, N.E., Chin, L. The INK4a/ARF locus and melanoma. Oncogene 22, 3092–3098 (2003). https://doi.org/10.1038/sj.onc.1206461
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206461
Keywords
This article is cited by
-
Artichoke as a melanoma growth inhibitor
Medical Oncology (2023)
-
Potential use of kiwifruit extract for treatment of melanoma
Medical Oncology (2021)
-
Frequent genetic defects in the p16/INK4A tumor suppressor in canine cell models of breast cancer and melanoma
In Vitro Cellular & Developmental Biology - Animal (2021)
-
Cellular senescence-mediated exacerbation of Duchenne muscular dystrophy
Scientific Reports (2020)
-
Response of human melanoma cell lines to interferon-beta gene transfer mediated by a modified adenoviral vector
Scientific Reports (2020)