Frontiers: PED/PEA-15, a multifunctional protein controlling cell survival and glucose metabolism

American Journal of Physiology - Endocrinology and Metabolism

Volumn 297, Issue 3, 2009, Pages

  Fiory, Francesca ^a   Formisano, Pietro ^a   Perruolo, Giuseppe ^a   Beguinot, Francesco ^a  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

Author keywords

Apoptosis; Insulin action; Type 2 diabetes

Indexed keywords

CALCIUM CALMODULIN DEPENDENT PROTEIN KINASE II; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; PHOSPHOPROTEIN; PROTEIN KINASE B; PROTEIN PEA 15; SERINE; UNCLASSIFIED DRUG;

APOPTOSIS; CANCER GROWTH; CARCINOGENESIS; CELL PROLIFERATION; CELL SURVIVAL; CELLULAR DISTRIBUTION; GLUCOSE METABOLISM; GLUCOSE TOLERANCE; HUMAN; INSULIN RELEASE; NEUROLOGIC DISEASE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REVIEW;

ANIMALS; APOPTOSIS; CELL PROLIFERATION; CELL SURVIVAL; CELL TRANSFORMATION, NEOPLASTIC; DIABETES MELLITUS, TYPE 2; GLUCOSE; GLUCOSE INTOLERANCE; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MODELS, BIOLOGICAL; NEOPLASMS; PHOSPHOPROTEINS;

EID: 69049103284     PISSN: 01931849     EISSN: 15221555     Source Type: Journal    
DOI: 10.1152/ajpendo.00228.2009     Document Type: Review

References (72)

1. Araujo H, Danziger N, Cordier J, Glowinski J, Chneiweiss H. Characterization of PEA-15, a major substrate for protein kinase C in astrocytes. J Biol Chem 268: 5911-5920, 1993.
2. Bardoux P, Zhang P, Flamez D, Perilhou A, Lavin TA, Tanti JF, Hellemans K, Gomas E, Godard C, Andreelli F, Buccheri MA, Kahn A, Le Marchand-Brustel Y, Burcelin R, Schuit F, Vasseur-Cognet M. Essential role of chicken ovalbumin upstream promoter-transcription factor II in insulin secretion and insulin sensitivity revealed by conditional gene knockout. Diabetes 54: 1357-1363, 2005.
3. Bartholomeusz C, Rosen D, Wei C, Kazansky A, Yamasaki F, Takahashi T, Itamochi H, Kondo S, Liu J, Ueno NT. PEA-15 induces autophagy in human ovarian cancer cells and is associated with prolonged overall survival. Cancer Res 68: 9302-9310, 2008.
4. Callaway K, Abramczyk O, Martin L, Dalby KN. The anti-apoptotic protein PEA-15 is a tight binding inhibitor of ERK1 and ERK2, which blocks docking interactions at the D-recruitment site. Biochemistry 46: 9187-9198, 2007.
5. Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VD. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81: 505-551, 1995.
6. Cicenas J. The potential role of Akt phosphorylation in human cancers. Int J Biol Markers 23: 1-9, 2008.
7. Condorelli G, Trencia A, Vigliotta G, Perfetti A, Goglia U, Cassese A, Musti AM, Miele C, Santopietro S, Formisano P, Beguinot F. Multiple members of the mitogen-activated protein kinase family are necessary for PED/PEA-15 anti-apoptotic function. J Biol Chem 277: 11013-11018, 2002.
8. Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andalò P, Oriente F, Miele C, Caruso M, Formisano P, Beguinot F. PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis. Oncogene 18: 4409-4415, 1999.
9. Condorelli G, Vigliotta G, Iavarone C, Caruso M, Tocchetti CG, Andreozzi F, Cafieri A, Tecce MF, Formisano P, Beguinot L, Beguinot F. PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus. EMBO J 17: 3858-3866, 1998.
10. Condorelli G, Vigliotta G, Trencia A, Maitan MA, Caruso M, Miele C, Oriente F, Santopietro S, Formisano P, Beguinot F. Protein kinase C (PKC)-alpha activation inhibits PKC-zeta and mediates the action of PED/PEA-15 on glucose transport in the L6 skeletal muscle cells. Diabetes 50: 1244-1252, 2001.
11. Danziger N, Yokoyama M, Jay T, Cordier J, Glowinski J, Chneiweiss H. Cellular expression, developmental regulation, and phylogenic conservation of PEA-15, the astrocytic major phosphoprotein and protein kinase C substrate. J Neurochem 64: 1016-1025, 1995.
12. Dong G, Loukinova E, Chen Z, Gangi L, Chanturita TI, Liu ET, Van Waes C. Molecular profiling of transformed and metastatic murine squamous carcinoma cells by differential display and cDNA microarray reveals altered expression of multiple genes related to growth, apoptosis, angiogenesis, and the NF-kappaB signal pathway. Cancer Res 61: 4797-4808, 2001.
13. Eramo A, Pallini R, Lotti F, Sette G, Patti M, Bartucci M, Ricci-Vitiani L, Signore M, Stassi G, Larocca LM, Crinò L, Peschle C, De Maria R. Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction. Cancer Res 65: 11469-11477, 2005.
14. Estellés A, Charlton CA, Blau HM. The phosphoprotein protein PEA-15 inhibits Fas- but increases TNF-R1-mediated caspase-8 activity and apoptosis. Dev Biol 216: 16-28, 1999.
15. Estellés A, Yokoyama M, Nothias F, Vincent JD, Glowinski J, Vernier P, Chneiweiss H. The major astrocytic phosphoprotein PEA-15 is encoded by two mRNAs conserved on their full length in mouse and human. J Biol Chem 271: 14800-14806, 1996.
16. Formisano P, Perruolo G, Libertini S, Santopietro S, Troncone G, Raciti GA, Oriente F, Portella G, Miele C, Beguinot F. Raised expression of the antiapoptotic protein ped/pea-15 increases susceptibility to chemically induced skin tumor development. Oncogene 24: 7012-7021, 2005.
17. Formstecher E, Ramos JW, Fauquet M, Calderwood DA, Hsieh JC, Canton B, Nguyen XT, Barnier JV, Camonis J, Ginsberg MH, Chneiweiss H. PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase. Dev Cell 1: 239-250, 2001.
18. Fraser JD, Martinez V, Straney R, Briggs MR. DNA binding and transcription activation specificity of hepatocyte nuclear factor 4. Nucleic Acids Res 26: 2702-2707, 1998.
19. Gaumont-Leclerc MF, Mukhopadhyay UK, Goumard S, Ferbeyre G. PEA-15 is inhibited by adenovirus E1A and plays a role in ERK nuclear export and Ras-induced senescence. J Biol Chem 279: 46802-46809, 2004.
20. Glading A, Koziol JA, Krueger J, Ginsberg MH. PEA-15 inhibits tumor cell invasion by binding to extracellular signal-regulated kinase 1/2. Cancer Res 67: 1536-1544, 2007.
21. Gupta RK, Kaestner KH. HNF-4alpha: from MODY to late-onset type 2 diabetes. Trends Mol Med 10: 521-524, 2004.
22. Hao C, Beguinot F, Condorelli G, Trencia A, Van Meir EG, Yong VW, Parney IF, Roa WH, Petruk KC. Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells. Cancer Res 61: 1162-1170, 2001.
23. Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21: 1393-1403, 2001.
24. Hill JM, Vaidyanathan H, Ramos JW, Ginsberg MH, Werner MH. Recognition of ERK MAP kinase by PEA-15 reveals a common docking site within the death domain and death effector domain. EMBO J 21: 6494-6504, 2002.
25. Hwang S, Kuo WL, Cochran JF, Guzman RC, Tsukamoto T, Bandyopadhyay G, Myambo K, Collins CC. Assignment of HMAT1, the human homolog of the murine mammary transforming gene (MAT1) associated with tumorigenesis, to 1q21.1, a region frequently gained in human breast cancers. Genomics 42: 540-542, 1997.
26. Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14: 5579-5588, 1995.
27. Kitsberg D, Formstecher E, Fauquet M, Kubes M, Cordier J, Canton B, Pan G, Rolli M, Glowinski J, Chneiweiss H. Knock-out of the neural death effector domain protein PEA-15 demonstrates that its expression protects astrocytes from TNFalpha-induced apoptosis. J Neurosci 19: 8244-8251, 1999.
28. Klein BE, Klein R, Moss SE, Cruickshanks KJ. Parental history of diabetes in a population-based study. Diabetes Care 19: 827-830, 1996.
29. Kubes M, Cordier J, Glowinski J, Girault JA, Chneiweiss H. Endothelin induces a calcium-dependent phosphorylation of PEA-15 in intact astrocytes: identification of Ser104 and Ser116 phosphorylated, respectively, by protein kinase C and calcium/calmodulin kinase II in vitro. J Neurochem 71: 1307-1314, 1998.
30. Laakso M, Zilinskaite J, Hansen T, Boesgaard TW, Vänttinen M, Stancáková A, Jansson PA, Pellmé F, Holst JJ, Kuulasmaa T, Hribal ML, Sesti G, Stefan N, Fritsche A, Häring H, Pedersen O, Smith U; EUGENE2 Consortium. Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study. Diabetologia 51: 502-511, 2008.
31. Lewis TS, Shapiro PS, Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res 74: 49-139, 1998.
32. Li L, Xie X, Qin J, Jeha GS, Saha PK, Yan J, Haueter CM, Chan L, Tsai SY, Tsai MJ. The nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis, and energy metabolism. Cell Metab 9: 77-87, 2009.
33. Martins LM, Morrison A, Klupsch K, Fedele V, Moisoi N, Teismann P, Abuin A, Grau E, Geppert M, Livi GP, Creasy CL, Martin A, Hargreaves I, Heales SJ, Okada H, Brandner S, Schulz JB, Mak T, Downward J. Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol Cell Biol 24: 9848-9862, 2004.
34. McCarthy MI. Casting a wider net for diabetes susceptibility genes. Nat Genet 40: 1039-1040, 2008.
35. Miele C, Raciti GA, Cassese A, Romano C, Giacco F, Oriente F, Paturzo F, Andreozzi F, Zabatta A, Troncone G, Bosch F, Pujol A, Chneiweiss H, Formisano P, Beguinot F. PED/PEA-15 regulates glucose-induced insulin secretion by restraining potassium channel expression in pancreatic beta-cells. Diabetes 56: 622-633, 2007.
36. Mietus-Snyder M, Sladek FM, Ginsburg GS, Kuo CF, Ladias JA, Darnell JE Jr, Karathanasis SK. Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells. Mol Cell Biol 12: 1708-1718, 1992.
37. Mitchell SM, Frayling TM. The role of transcription factors in maturity-onset diabetes of the young. Mol Genet Metab 77: 35-43, 2002.
38. Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85: 817-827, 1996.
39. Peacock JW, Palmer J, Fink D, Ip S, Pietras EM, Mui AL, Chung SW, Gleave ME, Cox ME, Parsons R, Peter ME, Ong CJ. PTEN loss promotes mitochondrially dependent type II Fas-induced apoptosis via PEA-15. Mol Cell Biol 29: 1222-1234, 2008.
40. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22: 153-183, 2001.
41. Pereira FA, Tsai MJ, Tsai SY. COUP-TF orphan nuclear receptors in development and differentiation. Cell Mol Life Sci 57: 1388-1398, 2000.
42. Perfetti A, Oriente F, Iovino S, Alberobello AT, Barbagallo AP, Esposito I, Fiory F, Teperino R, Ungaro P, Miele C, Formisano P, Beguinot F. Phorbol esters induce intracellular accumulation of the anti-apoptotic protein PED/PEA-15 by preventing ubiquitinylation and proteasomal degradation. J Biol Chem 282: 8648-8657, 2007.
43. Perilhou A, Tourrel-Cuzin C, Zhang P, Kharroubi I, Wang H, Fauveau V, Scott DK, Wollheim CB, Vasseur-Cognet M. The MODY1 gene for hepatocyte nuclear factor 4alpha and a feedback loop control COUP-TFII expression in pancreatic beta cells. Mol Cell Biol 28: 4588-4597, 2008.
44. Prokopenko I, McCarthy MI, Lindgren CM. Type 2 diabetes: new genes, new understanding. Trends Genet 24: 613-621, 2008.
45. Ramos JW, Hughes PE, Renshaw MW, Schwartz MA, Formstecher E, Chneiweiss H, Ginsberg MH. Death effector domain protein PEA-15 potentiates Ras activation of extracellular signal receptor-activated kinase by an adhesion-independent mechanism. Mol Biol Cell 11: 2863-2872, 2000.
46. Ramos JW, Kojima TK, Hughes PE, Fenczik CA, Ginsberg MH. The death effector domain of PEA-15 is involved in its regulation of integrin activation. J Biol Chem 273: 33897-33900, 1998.
47. Renault F, Formstecher E, Callebaut I, Junier MP, Chneiweiss H. The multifunctional protein PEA-15 is involved in the control of apoptosis and cell cycle in astrocytes. Biochem Pharmacol 66: 1581-1588, 2003.
48. Renault-Mihara F, Beuvon F, Iturrioz X, Canton B, De Bouard S, Léonard N, Mouhamad S, Sharif A, Ramos JW, Junier MP, Chneiweiss H. Phosphoprotein enriched in astrocytes-15 kDa expression inhibits astrocyte migration by a protein kinase C delta-dependent mechanism. Mol Biol Cell 17: 5141-5152, 2006.
49. Renganathan H, Vaidyanathan H, Knapinska A, Ramos JW. Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD. Biochem J 390: 729-735, 2005.
50. Song JH, Bellail A, Tse MC, Yong VW, Hao C. Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. J Neurosci 26: 3299-3308 [Erratum in J Neurosci 26: 4983, 2006].
51. Srinivasan BT, Jarvis J, Khunti K, Davies MJ. Recent advances in the management of type 2 diabetes mellitus: a review. Postgrad Med J 84: 524-531, 2008.
52. Srinivasula SM, Gupta S, Datta P, Zhang Z, Hegde R, Cheong N, Fernandes-Alnemri T, Alnemri ES. Inhibitor of apoptosis proteins are substrates for the mitochondrial serine protease Omi/HtrA2. J Biol Chem 278: 31469-31472, 2003.
53. Stassi G, Garofalo M, Zerilli M, Ricci-Vitiani L, Zanca C, Todaro M, Aragona F, Limite G, Petrella G, Condorelli G. PED mediates AKT-dependent chemoresistance in human breast cancer cells. Cancer Res 65: 6668-6675, 2005.
54. Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, Gasser T, Wszolek Z, Müller T, Bornemann A, Wolburg H, Downward J, Riess O, Schulz JB, Krüger R. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet 14: 2099-2111, 2005.
55. Trencia A, Fiory F, Maitan MA, Vito P, Barbagallo AP, Perfetti A, Miele C, Ungaro P, Oriente F, Cilenti L, Zervos AS, Formisano P, Beguinot F. Omi/HtrA2 promotes cell death by binding and degrading the anti-apoptotic protein ped/pea-15. J Biol Chem 279: 46566-46572, 2004.
56. Trencia A, Perfetti A, Cassese A, Vigliotta G, Miele C, Oriente F, Santopietro S, Giacco F, Condorelli G, Formisano P, Beguinot F. Protein kinase B/Akt binds and phosphorylates PED/PEA-15, stabilizing its antiapoptotic action. Mol Cell Biol 23: 4511-4521, 2003.
57. Tsukamoto T, Yoo J, Hwang SI, Guzman RC, Hirokawa Y, Chou YC, Olatunde S, Huang T, Bera TK, Yang J, Nandi S. Expression of MAT1/PEA-15 mRNA isoforms during physiological and neoplastic changes in the mouse mammary gland. Cancer Lett 149: 105-113, 2000.
58. Ungaro P, Teperino R, Mirra P, Cassese A, Fiory F, Perruolo G, Miele C, Laakso M, Formisano P, Beguinot F. Molecular cloning and characterization of the human PED/PEA-15 gene promoter reveal antagonistic regulation by hepatocyte nuclear factor 4alpha and chicken ovalbumin upstream promoter transcription factor II. J Biol Chem 283: 30970-30979, 2008.
59. Vaidyanathan H, Opoku-Ansah J, Pastorino S, Renganathan H, Matter ML, Ramos JW. ERK MAP kinase is targeted to RSK2 by the phosphoprotein PEA-15. Proc Natl Acad Sci USA 104: 19837-19842, 2007.
60. Vaidyanathan H, Ramos JW. RSK2 activity is regulated by its interaction with PEA-15. J Biol Chem 278: 32367-32372, 2003.
61. Valentino R, Lupoli GA, Raciti GA, Oriente F, Farinaro E, Della Valle E, Salomone M, Riccardi G, Vaccaro O, Donnarumma G, Sesti G, Hribal ML, Cardellini M, Miele C, Formisano P, Beguinot F. The PEA15 gene is overexpressed and related to insulin resistance in healthy first-degree relatives of patients with type 2 diabetes. Diabetologia 49: 3058-3066, 2006.
62. Vigliotta G, Miele C, Santopietro S, Portella G, Perfetti A, Maitan MA, Cassese A, Oriente F, Trencia A, Fiory F, Romano C, Tiveron C, Tatangelo L, Troncone G, Formisano P, Beguinot F. Overexpression of the ped/pea-15 gene causes diabetes by impairing glucose-stimulated insulin secretion in addition to insulin action. Mol Cell Biol 24: 5005-5015, 2004.
63. Viparelli F, Cassese A, Doti N, Paturzo F, Marasco D, Dathan NA, Monti SM, Basile G, Ungaro P, Sabatella M, Miele C, Teperino R, Consiglio E, Pedone C, Beguinot F, Formisano P, Ruvo M. Targeting of PED/PEA-15 molecular interaction with phospholipase D1 enhances insulin sensitivity in skeletal muscle cells. J Biol Chem 283: 21769-21778, 2008.
64. Viparelli F, Doti N, Sandomenico A, Marasco D, Dathan NA, Miele C, Beguinot F, Monti SM, Ruvo M. Expression and purification of the D4 region of PLD1 and characterization of its interaction with PED-PEA15. Protein Expr Purif 59: 302-308, 2008.
65. Whitehurst AW, Robinson FL, Moore MS, Cobb MH. The death effector domain protein PEA-15 prevents nuclear entry of ERK2 by inhibiting required interactions. J Biol Chem 279: 12840-12847, 2004.
66. Whitmer RA. Type 2 diabetes and risk of cognitive impairment and dementia. Curr Neurol Neurosci Rep 7: 373-380, 2007.
67. Wolford JK, Bogardus C, Ossowski V, Prochazka M. Molecular characterization of the human PEA15 gene on 1q21-q22 and association with type 2 diabetes mellitus in Pima Indians. Gene 241: 143-148, 2000.
68. Xiao C, Yang BF, Asadi N, Beguinot F, Hao C. Tumor necrosis factor-related apoptosis-inducing ligand-induced death-inducing signaling complex and its modulation by c-FLIP and PED/PEA-15 in glioma cells. J Biol Chem 277: 25020-25025, 2002.
69. Zabel C, Sagi D, Kaindl AM, Steireif N, Kläre Y, Mao L, Peters H, Wacker MA, Kleene R, Klose J. Comparative proteomics in neurodegenerative and non-neurodegenerative diseases suggest nodal point proteins in regulatory networking. J Proteome Res 5: 1948-1958, 2006.
70. Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G, Ardlie K, Boström KB, Bergman RN, Bonnycastle LL, Borch-Johnsen K, Burtt NP, Chen H, Chines PS, Daly MJ, Deodhar P, Ding CJ, Doney AS, Duren WL, Elliott KS, Erdos MR, Frayling TM, Freathy RM, Gianniny L, Grallert H, Grarup N, Groves CJ, Guiducci C, Hansen T, Herder C, Hitman GA, Hughes TE, Isomaa B, Jackson AU, Jørgensen T, Kong A, Kubalanza K, Kuruvilla FG, Kuusisto J, Langenberg C, Lango H, Lauritzen T, Li Y, Lindgren CM, Lyssenko V, Marvelle AF, Meisinger C, Midthjell K, Mohlke KL, Morken MA, Morris AD, Narisu N, Nilsson P, Owen KR, Palmer CN, Payne F, Perry JR, Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW, Rees M, Roix JJ, Sandbaek A, Shields B, Sjögren M, Steinthorsdottir V, Stringham HM, Swift AJ, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tuomi T, Tuomilehto J, Walker M, Watanabe RM, Weedon MN, Willer CJ; Wellcome Trust Case Control Consortium, Illig T, Hveem K, Hu FB, Laakso M, Stefansson K, Pedersen O, Wareham NJ, Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI, Boehnke M, Altshuler D. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40: 638-645, 2008.
71. Zhang Y, Redina O, Altshuller YM, Yamazaki M, Ramos J, Chneiweiss H, Kanaho Y, Frohman MA. Regulation of expression of phospholipase D1 and D2 by PEA-15, a novel protein that interacts with them. J Biol Chem 275: 35224-35232, 2000.
72. Zoumpourlis V, Solakidi S, Papathoma A, Papaevangeliou D. Alterations in signal transduction pathways implicated in tumor progression during multistage mouse skin carcinogenesis. Carcinogenesis 24: 1159-1165, 2003.