Cell Growth & Differentiation, Vol 4, Issue 5 367-376, Copyright © 1993 by American Association of Cancer Research

ARTICLES

Overexpression of wild-type p53 alters growth and differentiation of normal human keratinocytes but not human papillomavirus-expressing cell lines

CD Woodworth, H Wang, S Simpson, LM Alvarez-Salas and V Notario
Laboratory of Biology, National Cancer Institute, Bethesda, Maryland 20892.

To examine whether the tumor suppressor gene p53 influences epidermal differentiation, primary cultures of human foreskin keratinocytes and six human papillomavirus (HPV)-positive cell lines were infected with recombinant retroviruses encoding wild-type p53. Overexpression of p53 in organotypic cultures of normal keratinocytes decreased their growth rate and induced premature cell flattening and involucrin expression, a marker of squamous differentiation. However, overexpression of p53 inhibited or delayed production of other epidermal proteins, keratin 10, profilaggrin, and keratinocyte transglutaminase. Furthermore, levels of endogenous cellular p53 dramatically decreased during epidermal differentiation, suggesting that down-regulation of p53 permits complete expression of specific epidermal proteins. Three HPV-immortalized keratinocyte cell lines and three HPV-positive cervical carcinoma-derived cell lines expressed significantly less (< 3-fold) p53 protein than normal keratinocytes. Up-regulation of wild-type p53 (> 5-fold) by retrovirus infection did not significantly inhibit growth or restore normal epithelial differentiation in any line. Thus, overexpression of wild-type p53 can either induce or inhibit expression of specific epidermal proteins in normal keratinocytes but does not reverse immortality or aberrant differentiation of HPV-immortalized or carcinoma-derived cell lines.

This article has been cited by other articles:

				P. Mrass, M. Rendl, M. Mildner, F. Gruber, B. Lengauer, C. Ballaun, L. Eckhart, and E. Tschachler Retinoic Acid Increases the Expression of p53 and Proapoptotic Caspases and Sensitizes Keratinocytes to Apoptosis: A Possible Explanation for Tumor Preventive Action of Retinoids Cancer Res., September 15, 2004; 64(18): 6542 - 6548. [Abstract] [Full Text] [PDF]

				C. F. Wong, L. M. Barnes, A. L. Dahler, L. Smith, M. M. Serewko-Auret, C. Popa, I. Abdul-Jabbar, and N. A. Saunders E2F Modulates Keratinocyte Squamous Differentiation: IMPLICATIONS FOR E2F INHIBITION IN SQUAMOUS CELL CARCINOMA J. Biol. Chem., August 1, 2003; 278(31): 28516 - 28522. [Abstract] [Full Text] [PDF]

				M. Nees, J. M. Geoghegan, P. Munson, V. Prabhu, Y. Liu, E. Androphy, and C. D. Woodworth Human Papillomavirus Type 16 E6 and E7 Proteins Inhibit Differentiation-dependent Expression of Transforming Growth Factor-{beta}2 in Cervical Keratinocytes Cancer Res., August 1, 2000; 60(15): 4289 - 4298. [Abstract] [Full Text]

				T. Dilla, J. A. Velasco, D. L. Medina, J. F. Gonzalez-Palacios, and P. Santisteban The MDM2 Oncoprotein Promotes Apoptosis in p53-Deficient Human Medullary Thyroid Carcinoma Cells Endocrinology, January 1, 2000; 141(1): 420 - 429. [Abstract] [Full Text] [PDF]

				S. K. Gilmour, M. Birchler, M. K. Smith, K. Rayca, and J. Mostochuk Effect of Elevated Levels of Ornithine Decarboxylase on Cell Cycle Progression in Skin Cell Growth Differ., November 1, 1999; 10(11): 739 - 748. [Abstract] [Full Text]

				H. Ben-Bassat, S. Rosenbaum-Mitrani, Z. Hartzstark, R. Levitzki, M. Chaouat, Z. Shlomai, B. Y. Klein, N. Kleinberger-Doron, A. Gazit, R. Tsvieli, et al. Tyrphostins That Suppress the Growth of Human Papilloma Virus 16-Immortalized Human Keratinocytes J. Pharmacol. Exp. Ther., September 1, 1999; 290(3): 1442 - 1457. [Abstract] [Full Text]

				P. Ruiz-Lozano, M. L. Hixon, M. W. Wagner, A. I. Flores, S. Ikawa, A. S. Baldwin Jr., K. R. Chien, and A. Gualberto p53 Is a Transcriptional Activator of the Muscle-specific Phosphoglycerate Mutase Gene and Contributesin Vivo to the Control of Its Cardiac Expression Cell Growth Differ., May 1, 1999; 10(5): 295 - 306. [Abstract] [Full Text]

				A J Wagner, J M Kokontis, and N Hay Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. Genes & Dev., December 1, 1994; 8(23): 2817 - 2830. [Abstract] [PDF]