Abstract
Differentiation of cells is typically marked by a cessation of proliferation with a concurrent entrance into a distinct metabolic state marked by tissue specific gene expression. The mechanism by which the cell exits the cell cycle in this process is poorly understood. To determine the potential roles of the cell cycle machinery in the regulation of the terminal differentiation process of epidermal cells, we selected a well characterized in vitro model in which primary mouse keratinocytes are induced to differentiate in response to a raised calcium ion concentration in the medium. The withdrawal from the cell cycle correlates very well with a number of changes in the cell cycle machinery. Changes in the phosphorylation status of the Rb family of proteins occurs coordinately with an increased association of p21, p27 and p57 with cdk2. Furthermore, we find that inhibition of cdk2 activity is not sufficient to elicit changes that occur during keratinocyte differentiation. Finally, the previously described v-Ha-ras block of keratinocyte differentiation correlates with altered regulation of both cyclin D1 and cdk2 suggesting that these genes may play a role in the Ha-ras transformation of a keratinocyte.
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References
Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A and Pestell RG. . 1995 J. Biol. Chem. 270: 23589–23597.
Bianchi AB, Fischer SM, Robles AI, Rinchik EM and Conti CJ. . 1993 Oncogene 8: 1127–1133.
Botz J, Zerfass-Thome K, Spitkovsky D, Delius H, Vogt B, Eilers M, Hatzigeorgiou A and Jansen-Durr P. . 1996 Mol. Cell. Biol. 16: 3401–3409.
Chin L, Schreiber-Agus N, Pellicer I, Chen K, Lee HW, Dudast M, Cordon-Cardo C and De Pinho RA. . 1995 Proc. Natl. Acad. Sci. USA 92: 8488–8492.
Clarke AR, Maandag ER, Van Roon M, Van der Lugt NMT, Van der Valk M, Hooper ML, Berns A and Riele H. . 1992 Nature 359: 328–330.
Cobrinik D, Lee M, Hannon G, Mulligan G, Bronson R, Dyson N, Harlow E, Beach D, Weinberg R and Jacks T. . 1996 Genes Dev. 10: 1633–1644.
Deng C, Zhang P, Harper JW, Elledge SJ and Leder P. . 1995 Cell 82: 675–684.
Ewen ME, Sluss HK, Sherr CJ, Matsushime H, Kato J and Livingston DM. . 1993 Cell 73: 487–497.
Filmus J, Robles AI, Shi W, Wong MJ, Colombo LL and Conti CJ. . 1994 Oncogene 12: 3627–3633.
Gotz C, Wagner P, Issinger O-G and Montenarh M. . 1996 Oncogene 13: 391–398.
Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon G, Beach D and Lassar AB. . 1995 Science 267: 1018–1021.
Hall M, Bates S and Peters G. . 1995 Oncogene 11: 1581–1588.
Hauser P, Agrawal D, Flanagan M and Pledger W. . 1997 Cell Growth Differ. 8: 203–211.
Hennings H, Michael D, Cheng C, Steiner P, Holbrook K and Yuspa SH. . 1980 Cell 19: 245–254.
Hurlin PJ, Foley KP, Ayer DE, Eisenman RN, Hanahan D and Arbeit JM. . 1995 Oncogene 11: 2487–2501.
Hurford RJ, Cobrinik D, Lee M and Dyson N. . 1997 Genes Dev. 11: 1447–1463.
Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA and Weinberg RA. . 1992 Nature 359: 295–300.
Jiang H, Lin J, Su SS, Collart FR, Huberman E and Fisher PB. . 1994 Oncogene 9: 3397–3406.
Kato JY, Matsuoka M, Polyak K, Massague J and Sherr C. . 1994a Cell 79: 487–496.
Kato JY, Matsuoka M, Strom DK and Sherr C. . 1994b Mol. Cell. Biol. 14: 2713–2721.
Kiess M, Gill MR and Hamel PA. . 1995 Oncogene 10: 159–166.
Koff A, Giordano D, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR and Roberts JM. . 1992 Science 257: 1689–1694.
Kranenburg O, van der Eb AJ and Zantema A. . 1995 FEBS Letts 367: 103–106.
Lee EYHP, Chang CY, Hu N, Wang YCJ, Lai CC, Herrup K, Lee WH and Bradley A. . 1992 Nature 359: 288–294.
Lee MH, Nikolic M, Baptista CA, Lai E, Tsai L-H and Massague J. . 1996 Proc. Natl. Acad. Sci. USA 93: 3259–3263.
Lew DJ, Dulic V and Reed SI. . 1991 Cell 66: 1197–1206.
Lin J, Reichner C, Wu X and Levine AJ. . 1996 Mol. Cell. Biol. 16: 1786–1793.
Liu JJ, Chao JR, Jiang MC, Ng SY, Yen JJ and Yang-Yen HF. . 1995 Mol. Cell. Biol. 15: 3654–3663.
Lukas J, Bartkova J, Rohde M, Strauss M and Bartek J. . 1995 Mol. Cell. Biol. 15: 2600–2611.
Matsushime H, Roussel MF, Ashmun RA and Sherr CJ. . 1991 Cell 65: 701–713.
Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ and Kato JA. . 1994 Mol. Cell. Biol. 14: 2066–2076.
Meijer L, Borgne A, Mulner O, Chong J, Blow J, Inagaki N, Inagaki M, Delcros J and Moulinoux J. . 1997 Eur. J. Biochem. 243: 527–536.
Missero C, Calautti E, Eckner R, Chin J, Tsai LH, Livingston DM and Dotto GP. . 1995 Proc. Natl. Acad. Sci. USA 92: 5451–5455.
Missero C, Di Cunto F, Kiyokawa H, Koff A and Dotto GP. . 1996 Genes Dev. 10: 3065–3075.
Morgan DO. . 1995 Nature 374: 131–134.
Muller H, Lukas J, Scheider A, Warthoe P, Bartek J, Eilers M and Strauss M. . 1994 Proc. Natl. Acad. Sci. USA 91: 2945–2949.
Ohtsubo M, Theodoras AM, Shumacker J, Roberts JM and Pagano M. . 1995 Mol. Cell. Biol. 15: 2612–2627.
Robles AI and Conti CJ. . 1995 Carcinogenesis 16: 781–786.
Sambrook J, Fritsch EF and Maniatis T. . 1989 Cold Springs Harbor Lab. Press.
Schneider JW, Gu W, Zhu L, Mahdavi V and Nadal-Ginard B. . 1994 Science 264: 1467–1471.
Sherr CJ. . 1994 Cell 79: 557–562.
Sherr CJ and Roberts JM. . 1995 Genes Dev. 9: 1149–1163.
Shim J, Lee H, Park J, Kim H and Choi E-J. . 1996 Nature 381: 804–807.
SteinMan RA, Hoffman B, Iro A, Guillouf C, Liebermann DA and El-Houseini ME. . 1994 Oncogene 9: 3389–3396.
Vastrik I, Kaipainen A, Penttila TL, Lymboussakis A, Alitalo R, Parvinen M and Alitalo K. . 1995 J. Cell Biol. 128: 1197–1208.
Weinberg RA. . 1995 Cell 81: 323–330.
Weinberg WC, Azzoli CG, Chapman K, Levine AJ and Yuspa SH. . 1995 Oncogene 10: 2271–2279.
Xiong Y, Connolly T, Futcher B and Beach D. . 1991 Cell 65: 691–699.
Yuspa SH, Kilkenny AE, Stanley J and Lichti U. . 1985 Nature 314: 459–462.
Acknowledgements
We would like to thank Melissa Bracher for helping with the preparation of this manuscript, Judy G Ing and the Art Department for the art work, Marilyn Lee for culture setups, Dr Charles Sherr for providing antibodies and cDNA probes, Dr Dennis Roop for providing Keratin antibodies, Dr Stuart Yuspa for providing the retrovirus packaging cells and David Nors for his technical advice. We also want to thank Dr Laurent Meijer for generously providing roscovitine and for providing us with unpublished results. This work was supported by grants from the National Cancer Institute CA 42157 and CA 57596.
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Martinez, L., Chen, Y., Fischer, S. et al. Coordinated changes in cell cycle machinery occur during keratinocyte terminal differentiation. Oncogene 18, 397–406 (1999). https://doi.org/10.1038/sj.onc.1202300
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DOI: https://doi.org/10.1038/sj.onc.1202300
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