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Topological Control of p21^WAF1/CIP1 Expression in Normal and Neoplastic Tissues¹

The Oncology Center and Program in Human Genetics and Molecular Biology. The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231 [W. S. E-D., T. T., T. W., J. D. O., V. E. V., K. W. K., B. V.]; Howard Hughes Medical Institute [W. S. E-D., B. V.] and Department of Medicine and Genetics, [W. S. E-D.] University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Oncogene Science, Inc., Cambridge, Massachusetts 02142 [M. B., D. E. H.]; Department of Dermatology, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom NEI4LP [E. H., J. L. R.]; and Department of Pathology and Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 [S. R. H.]

The p53-regulated gene product p21^WAF1/CIP1 is the prototype of a family of small proteins that negatively regulate the cell cycle. To learn more about p21^WAF1/CIP1 regulation in vivo, monoclonal antibodies were developed for immunohistochemistry. These revealed that p21^WAF1/CIP1 expression followed radiation-induced DNA damage in human skin in a pattern consistent with its regulation by p53. A detailed comparison of the human, rat, and mouse p21^WAF1/CIP1 promoter sequences revealed that this induction was probably mediated by conserved p53-binding sites upstream of the transcription start site. In unirradiated tissues, p21^WAF1/CIP1 expression was apparently independent of p53 and was observed in a variety of cell types. Moreover, there was a striking compartmentalization of p21^WAF1/CIP1 expression throughout the gastrointestinal tract that correlated with proliferation rather than differentiation. As epithelial cells migrated up the crypts, the K167-expressing proliferating compartment near the crypt base ended abruptly, with the coincident appearance of a nonproliferating compartment expressing p21^WAF1/CIP1. In colonic neoplasms, this distinct compartmentalization was largely abrogated. Cell cycle inhibitors are thus subject to precise topological control, and escape from this regulation may be a critical feature of neoplastic transformation.

¹ This work was supported by NIH Grants GM07184, CA43460, and CA62924 (to B. V.) and by MRC and NECRC (to J. L. R.). W. S. E-D. is an Assistant Investigator and B. V. is an Investigator of the Howard Hughes Medical Institute, B. V. is an American Cancer Society Research Professor.

² The first two authors contributed equally to this work.

³ To whom requests for reprints should be addressed, at Molecular Genetics Laboratory, The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231-1001.

Received 4/21/95. Accepted 4/27/95.

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				J. Liu, X. Shen, V.-A. Nguyen, G. Kunos, and B. Gao alpha 1 Adrenergic Agonist Induction of p21waf1/cip1 mRNA Stability in Transfected HepG2 Cells Correlates with the Increased Binding of an AU-rich Element Binding Factor J. Biol. Chem., April 14, 2000; 275(16): 11846 - 11851. [Abstract] [Full Text] [PDF]

				B.-D. Chang, K. Watanabe, E. V. Broude, J. Fang, J. C. Poole, T. V. Kalinichenko, and I. B. Roninson Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: Implications for carcinogenesis, senescence, and age-related diseases PNAS, April 11, 2000; 97(8): 4291 - 4296. [Abstract] [Full Text] [PDF]

				S Siavoshian, J-P Segain, M Kornprobst, C Bonnet, C Cherbut, J-P Galmiche, and H M Blottiere Butyrate and trichostatin A effects on the proliferation/differentiation of human intestinal epithelial cells: induction of cyclin D3 and p21 expression Gut, April 1, 2000; 46(4): 507 - 514. [Abstract] [Full Text] [PDF]

				A. Yoshida, R. R. Newbold, and D. Dixon Abnormal Cell Differentiation and p21 Expression of Endometrial Epithelial Cells Following Developmental Exposure to Diethylstilbestrol (DES) Toxicol Pathol, March 1, 2000; 28(2): 237 - 245. [Abstract] [PDF]

				L. A. Allan, T. Duhig, M. Read, and M. Fried The p21WAF1/CIP1 Promoter Is Methylated in Rat-1 Cells: Stable Restoration of p53-Dependent p21WAF1/CIP1 Expression after Transfection of a Genomic Clone Containing the p21WAF1/CIP1 Gene Mol. Cell. Biol., February 15, 2000; 20(4): 1291 - 1298. [Abstract] [Full Text]

				Y. Shirakawa, Y. Naomoto, M. Kimura, R. Kawashima, T. Yamatsuji, T. Tamaki, M. Hamada, M. Haisa, and N. Tanaka Topological Analysis of p21WAF1/CIP1 Expression in Esophageal Squamous Dysplasia Clin. Cancer Res., February 1, 2000; 6(2): 541 - 550. [Abstract] [Full Text]

				J. L. Schwartz Biomarkers and Molecular Epidemiology and Chemoprevention of Oral Carcinogenesis Critical Reviews in Oral Biology & Medicine, January 1, 2000; 11(1): 92 - 122. [Abstract] [Full Text] [PDF]

				T. Sukata, K. Ozaki, S. Uwagawa, T. Seki, H. Wanibuchi, S. Yamamoto, Y. Okuno, and S. Fukushima Organ-specific, Carcinogen-induced Increases in Cell Proliferation in p53-deficient Mice Cancer Res., January 1, 2000; 60(1): 74 - 79. [Abstract] [Full Text]

				K. Sonoyama, S. Rutatip, and T. Kasai Gene expression of activin, activin receptors, and follistatin in intestinal epithelial cells Am J Physiol Gastrointest Liver Physiol, January 1, 2000; 278(1): G89 - G97. [Abstract] [Full Text] [PDF]

				E. C. Thornborrow and J. J. Manfredi One Mechanism for Cell Type-specific Regulation of the bax Promoter by the Tumor Suppressor p53 Is Dictated by the p53 Response Element J. Biol. Chem., November 19, 1999; 274(47): 33747 - 33756. [Abstract] [Full Text] [PDF]

				F. Beier, A. C. Taylor, and P. LuValle The Raf-1/MEK/ERK Pathway Regulates the Expression of the p21Cip1/Waf1 Gene in Chondrocytes J. Biol. Chem., October 15, 1999; 274(42): 30273 - 30279. [Abstract] [Full Text] [PDF]

				D. Kardassis, P. Papakosta, K. Pardali, and A. Moustakas c-Jun Transactivates the Promoter of the Human p21WAF1/Cip1 Gene by Acting as a Superactivator of the Ubiquitous Transcription Factor Sp1 J. Biol. Chem., October 8, 1999; 274(41): 29572 - 29581. [Abstract] [Full Text] [PDF]

				G. Pruneri, L. Pignataro, N. Carboni, R. Buffa, D. Di Finizio, B. M. Cesana, and A. Neri Clinical Relevance of Expression of the CIP/KIP Cell-Cycle Inhibitors p21 and p27 in Laryngeal Cancer J. Clin. Oncol., October 1, 1999; 17(10): 3150 - 3159. [Abstract] [Full Text] [PDF]

				M. E. Saunders, R. MacKenzie, R. Shipman, E. Fransen, R. Gilbert, and R. C. K. Jordan Patterns of p53 Gene Mutations in Head and Neck Cancer: Full-Length Gene Sequencing and Results of Primary Radiotherapy Clin. Cancer Res., September 1, 1999; 5(9): 2455 - 2463. [Abstract] [Full Text] [PDF]

				G. Paolo Dotto Signal Transduction Pathways Controlling the Switch Between Keratinocyte Growth and Differentiation Critical Reviews in Oral Biology & Medicine, July 1, 1999; 10(4): 442 - 457. [Abstract] [Full Text] [PDF]

				T. Taniguchi, H. Endo, N. Chikatsu, K. Uchimaru, S. Asano, T. Fujita, T. Nakahata, and T. Motokura Expression of p21Cip1/Waf1/Sdi1 and p27Kip1 Cyclin-Dependent Kinase Inhibitors During Human Hematopoiesis Blood, June 15, 1999; 93(12): 4167 - 4178. [Abstract] [Full Text] [PDF]

				R. Mirzayans, S. Bashir, D. Murray, and M. C. Paterson Inverse correlation between p53 protein levels and DNA repair efficiency in human fibroblast strains treated with 4-nitroquinoline 1-oxide: evidence that lesions other than DNA strand breaks trigger the p53 response Carcinogenesis, June 1, 1999; 20(6): 941 - 946. [Abstract] [Full Text] [PDF]

				J. Q. Tian and A. Quaroni Involvement of p21(WAF1/Cip1) and p27(Kip1) in intestinal epithelial cell differentiation Am J Physiol Cell Physiol, June 1, 1999; 276(6): C1245 - C1258. [Abstract] [Full Text] [PDF]

				J. D. heng, B. A. Werness, J. S. Babb, and N. J. Meropol Paradoxical Correlations of Cyclin-dependent Kinase Inhibitors p21waf1/cip1 and p27kip1 in Metastatic Colorectal Carcinoma Clin. Cancer Res., May 1, 1999; 5(5): 1057 - 1062. [Abstract] [Full Text] [PDF]

				Y. Zhang, M. B. Dickman, and C. Jones The Mycotoxin Fumonisin B1 Transcriptionally Activates the p21 Promoter through a cis-Acting Element Containing Two Sp1 Binding Sites J. Biol. Chem., April 30, 1999; 274(18): 12367 - 12371. [Abstract] [Full Text] [PDF]

				O. Eickelberg, M. Roth, R. Lorx, V. Bruce, J. Rudiger, M. Johnson, and L.-H. Block Ligand-independent Activation of the Glucocorticoid Receptor by beta 2-Adrenergic Receptor Agonists in Primary Human Lung Fibroblasts and Vascular Smooth Muscle Cells J. Biol. Chem., January 8, 1999; 274(2): 1005 - 1010. [Abstract] [Full Text] [PDF]

				F. Bunz, A. Dutriaux, C. Lengauer, T. Waldman, S. Zhou, J. P. Brown, J. M. Sedivy, K. W. Kinzler, and B. Vogelstein Requirement for p53 and p21 to Sustain G2 Arrest After DNA Damage Science, November 20, 1998; 282(5393): 1497 - 1501. [Abstract] [Full Text]

				H.-y. Tang, K. Zhao, J. F. Pizzolato, M. Fonarev, J. C. Langer, and J. J. Manfredi Constitutive Expression of the Cyclin-dependent Kinase Inhibitor p21 Is Transcriptionally Regulated by the Tumor Suppressor Protein p53 J. Biol. Chem., October 30, 1998; 273(44): 29156 - 29163. [Abstract] [Full Text] [PDF]

				J.-L. Tsao, J. Zhang, R. Salovaara, Z.-H. Li, H. J. Jarvinen, J.-P. Mecklin, L. A. Aaltonen, and D. Shibata Tracing Cell Fates in Human Colorectal Tumors from Somatic Microsatellite Mutations : Evidence of Adenomas with Stem Cell Architecture Am. J. Pathol., October 1, 1998; 153(4): 1189 - 1200. [Abstract] [Full Text] [PDF]

				A. M. De Marzo, A. K. Meeker, J. I. Epstein, and D. S. Coffey Prostate Stem Cell Compartments : Expression of the Cell Cycle Inhibitor p27Kip1 inNormal, Hyperplastic, and Neoplastic Cells Am. J. Pathol., September 1, 1998; 153(3): 911 - 919. [Abstract] [Full Text] [PDF]