| Gain of cellular adaptation due to prolonged p53 impairment leads to functional switchover from p53 to p73 during DNA damage in acute myeloid leukemia cells. | |
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MedLine Citation:
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PMID: 20675383 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Tumor suppressor p53 plays the central role in regulating apoptosis in response to genotoxic stress. From an evolutionary perspective, the activity of p53 has to be backed up by other protein(s) in case of any functional impairment of this protein, to trigger DNA damage-induced apoptosis in cancer cells. We adopted multiple experimental approaches to demonstrate that in p53-impaired cancer cells, DNA damage caused accumulation of p53 paralogue p73 via Chk-1 that strongly impacted Bax expression and p53-independent apoptosis. On the contrary, when p53 function was restored by ectopic expression, Chk-2 induced p53 accumulation that in turn overshadowed p73 activity, suggesting an antagonistic interaction between p53 family members. To understand such interaction better, p53-expressing cells were impaired differentially for p53 activity. In wild-type p53-expressing cancer cells that were silenced for p53 for several generations, p73 was activated, whereas no such trend was observed when p53 was transiently silenced. Prolonged p53 interference, even in functional p53 settings, therefore, leads to the "gain of cellular adaptation" in a way that alters the cellular microenvironment in favor of p73 activation by altering p73-regulatory proteins, e.g. Chk1 activation and dominant negative p73 down-regulation. These findings not only unveil a hitherto unexplained mechanism underlying the functional switchover from p53 to p73, but also validate p73 as a promising and potential target for cancer therapy in the absence of functional p53. |
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Authors:
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Juni Chakraborty; Shuvomoy Banerjee; Pallab Ray; Dewan Md Sakib Hossain; Sankar Bhattacharyya; Arghya Adhikary; Sreya Chattopadhyay; Tanya Das; Gaurisankar Sa |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-30 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-18 Completed Date: 2010-11-24 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 33104-12 Citation Subset: IM |
Affiliation:
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Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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genetics DNA Damage* DNA-Binding Proteins / genetics, metabolism* Gene Expression Regulation, Leukemic / genetics Gene Silencing HL-60 Cells Humans Leukemia, Myeloid, Acute / genetics, metabolism*, therapy Nuclear Proteins / genetics, metabolism* Protein Kinases / biosynthesis, genetics Time Factors Tumor Suppressor Protein p53 / genetics, metabolism* Tumor Suppressor Proteins / genetics, metabolism* U937 Cells bcl-2-Associated X Protein / biosynthesis, genetics |
| Chemical | |
Reg. No./Substance:
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0/BAX protein, human; 0/DNA-Binding Proteins; 0/Nuclear Proteins; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; 0/bcl-2-Associated X Protein; 0/tumor suppressor protein p73; EC 2.7.-/Protein Kinases; EC 2.7.11.1/Checkpoint kinase 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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