Activities and Response to DNA Damage of Latent and Active Sequence-Specific DNA Binding Forms of Mouse p53

The mouse p53 protein generated by alternative splicing (p53as) has amino acid substitutions at its C terminus that result in constitutively active sequence-specific DNA binding (active form), whereas p53 protein itself binds inefficiently (latent form) unless activated by C-terminal modification. E...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-08, Vol.94 (17), p.8982-8987
Main Authors: Wu, Yu, Huang, Hua, Miner, Zoe, Kulesz-Martin, Molly
Format: Article
Language:English
Subjects:
Animals
Antibodies
Biological Sciences
Cell Division - genetics
Cell growth
Cell Line
Cellular immunity
Deoxyribonucleic acid
DNA
DNA Damage
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Epidermal cells
Fibroblasts
Genes
Humans
Immunoblotting
Injuries
Messenger RNA
Mice
Molecular biology
Plasmids
Proteins
Rodents
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:The mouse p53 protein generated by alternative splicing (p53as) has amino acid substitutions at its C terminus that result in constitutively active sequence-specific DNA binding (active form), whereas p53 protein itself binds inefficiently (latent form) unless activated by C-terminal modification. Exogenous p53as expression activated transcription of reporter plasmids containing p53 binding sequences and inhibited growth of mouse and human cells lacking functional endogenous p53. Inducible p53as in stably transfected p53 null fibroblasts increased p21WAF1/Cip-1/Sdiand decreased bcl-2 protein steady-state levels. Endogenous p53as and p53 proteins differed in response to cellular DNA damage. p53 protein was induced transiently in normal keratinocytes and fibroblasts whereas p53as protein accumulation was sustained in parallel with induction of p21WAF1/Cip-1/Sdiprotein and mRNA, in support of p53as transcriptional activity. Endogenous p53 and p53as proteins in epidermal tumor cells responded to DNA damage with different kinetics of nuclear accumulation and efficiencies of binding to a p53 consensus DNA sequence. A model is proposed in which C-terminally distinct p53 protein forms specialize in functions, with latent p53 forms primarily for rapid non-sequence-specific binding to sites of DNA damage and active p53 forms for sustained regulation of transcription and growth.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.17.8982