Promyelocytic leukemia activates Chk2 by mediating Chk2 autophosphorylation Journal Article
| Authors: | Yang, S.; Jeong, J. H.; Brown, A. L.; Lee, C. H.; Pandolfi, P. P.; Chung, J. H.; Kim, M. K. |
| Article Title: | Promyelocytic leukemia activates Chk2 by mediating Chk2 autophosphorylation |
| Abstract: | Chk2 is a kinase critical for DNA damage-induced apoptosis and is considered a tumor suppressor. Chk2 is essential for p53 transcriptional and apoptotic activities. Although mutations of p53 are present in more than half of all tumors, mutations of Chk2 in cancers are rare, suggesting that Chk2 may be inactivated by unknown alternative mechanisms. Here we elucidate one such alternative mechanism regulated by PML (promyelocytic leukemia) that is involved in acute promyelocytic leukemia (APL). Although p53-inactivating mutations are extremely rare in APL, t(15;17) chromosomal translocation which fuses retinoic acid receptor (RARα) to PML is almost always present in APL, while the other PML allele is intact. We demonstrate that PML interacts with Chk2 and activates Chk2 by mediating its autophosphorylation step, an essential step for Chk2 activity that occurs after phosphorylation by the upstream kinase ATM (ataxia telangiectasia-mutated). PML/RARα in APL suppresses Chk2 by dominantly inhibiting the autophosphorylation step, but inactivation of PML/RARα with all-trans retinoic acid (ATRA) restores Chk2 autophosphorylation and activity. Thus, by fusing PML with RARα, the APL cells appear to have achieved functional suppression of Chk2 compromising the Chk2-p53 apoptotic pathway. |
| Keywords: | immunohistochemistry; controlled study; gene mutation; dna-binding proteins; nonhuman; antineoplastic agents; proteins; animal cell; mouse; animals; cell cycle proteins; mice; mice, knockout; allele; apoptosis; gene expression; embryo; enzyme activation; enzyme activity; hela cells; autophosphorylation; phosphorylation; protein p53; mice, inbred c57bl; transcription factors; nuclear proteins; leukemia, promyelocytic, acute; dna; enzyme phosphorylation; regulatory mechanism; recombinant fusion proteins; tumors; protein-serine-threonine kinases; tumor suppressor proteins; promyelocytic leukemia; oncogene proteins, fusion; tumor suppressor protein p53; chromosome translocation; checkpoint kinase 2; disease control; retinoic acid; mutagenesis; chromosomes; phosphorescence; ataxia telangiectasia; retinoic acid receptor alpha; cells; acute promyelocytic leukemia (apl); tretinoin; receptors, retinoic acid; ataxia telangiectasia mutated (atm); promyelocytic leukemia (pml); retinoic acid receptor (rarα) |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 281 |
| Issue: | 36 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2006-09-08 |
| Start Page: | 26645 |
| End Page: | 26654 |
| Language: | English |
| DOI: | 10.1074/jbc.M604391200 |
| PUBMED: | 16835227 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 19" - "Export Date: 4 June 2012" - "CODEN: JBCHA" - "Source: Scopus" |
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