p53-Dependent and independent expression of p21 during cell growth, differentiation, and DNA damage

Macleod, K. F., Sherry, N., Hannon, G., Beach, D., Tokino, T., Kinzler, K., Vogelstein, B., Jacks, T. (1995) p53-Dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes and Development, 9 (8). pp. 935-944. ISSN 08909369

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Abstract

Expression of p21 has been shown to be up-regulated by the p53 tumor suppressor gene in vitro in response to DNA-damaging agents. However, p21 expression can be regulated independently of p53, and here we show that expression of p21 in various tissues during development and in the adult mouse occurs in the absence of p53 function. However, most tissues tested did require p53 for p21 induction following exposure of the whole animal to γ irradiation. These results show that normal tissue expression of p21 to high levels is not dependent on p53 and confirm that induction of p21 by DNA- damaging agents does require p53. p21 is expressed upon differentiation of p53-deficient murine erythroleukemia (MEL) cells, and the kinetics of induction of p21 in this system suggest that it may be involved in the growth arrest that precedes terminal differentiation. The gene is up-regulated in mouse fibroblasts in response to serum restimulation but the kinetics and levels of induction differ between wild-type and mutant cells. Expression of p21 message following serum restimulation is superinducible by cycloheximide in wild-type but not in p53-deficient cells. The increases in p21 mRNA are reflected in changes in p21 protein levels. p21 expression also appears to be regulated at the post-transcriptional level because moderate increases in mRNA expression, during differentiation of MEL cells and upon serum restimulation of fibroblasts, are followed by large increases in protein levels. Regulation of the mouse p21 promoter by p53 depends on two critical p53-binding sites located 1.95 and 2.85 kb upstream from the transcriptional initiation site. The sequences mediating serum responsiveness of the promoter map to a region containing the proximal p53 site. p53 appears to play a critical role in p21 induction following DNA damage. Moreover, p21 can be regulated independently of p53 in several situations including during normal tissue development, following serum stimulation, and during cellular differentiation.

Item Type:	Paper
Uncontrolled Keywords:	cellular differentiation DNA damage p21 p53 chloramphenicol acetyltransferase cyclin dependent kinase cycloheximide dimethyl sulfoxide dna glyceraldehyde 3 phosphate dehydrogenase hexamethylenebisacetamide histone h1 messenger rna methionine protamine kinase protein p21 protein p53 adolescent animal cell animal tissue article cell differentiation cell growth controlled study embryo erythroleukemia cell fibroblast gamma irradiation gene expression mouse nonhuman priority journal promoter region serum tissue distribution tumor suppressor gene Animal Base Sequence Binding Sites Cell Division Cells Cultured Culture Media Cyclin Dependent Kinases Cyclins Gene Expression Regulation Mice Molecular Sequence Data Promoter Regions Genetics Protein Binding RNA Messenger Support Non U S Govt
Subjects:	bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation organism description > animal > mammal > rodent > mouse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p21 bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
CSHL Authors:	Hannon, Gregory J.
Communities:	CSHL labs > Hannon lab CSHL labs > Beach lab
Depositing User:	Editor Margaret Fantz
Date:	1995
Date Deposited:	16 Apr 2012 19:32
Last Modified:	02 Dec 2016 19:35
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/26118

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