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Mar. Drugs 2015, 13(6), 3625-3639; doi:10.3390/md13063625

Activation of RAF1 (c-RAF) by the Marine Alkaloid Lasonolide A Induces Rapid Premature Chromosome Condensation

1
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute (CCR-NCI), NIH, Bethesda, MD 20892-9760, USA
2
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute (CCR-NCI), NIH, Bethesda, MD 20892-9760, USA
3
Departments of Chemistry and Medicinal Chemistry, Purdue University; West Lafayette, IN 47907, USA
Present address: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
*
Authors to whom correspondence should be addressed.
Academic Editor: Angela Capper
Received: 25 March 2015 / Revised: 18 May 2015 / Accepted: 26 May 2015 / Published: 5 June 2015
(This article belongs to the Special Issue Okadaic Acid and Dinophysis Toxins)
View Full-Text   |   Download PDF [2034 KB, uploaded 5 June 2015]   |  

Abstract

Lasonolide A (LSA), a potent antitumor polyketide from the marine sponge, Forcepia sp., induces rapid and reversible protein hyperphosphorylation and premature chromosome condensation (PCC) at nanomolar concentrations independent of cyclin-dependent kinases. To identify cellular targets of LSA, we screened 2951 shRNAs targeting a pool of human kinases and phosphatases (1140 RefSeqs) to identify genes that modulate PCC in response to LSA. This led to the identification of RAF1 (C-RAF) as a mediator of LSA-induced PCC, as shRNAs against RAF1 conferred resistance to LSA. We found that LSA induced RAF1 phosphorylation on Serine 338 within minutes in human colorectal carcinoma HCT-116, ovarian carcinoma OVCAR-8, and Burkitt’s lymphoma CA46 cell lines. RAF1 depletion by siRNAs attenuated LSA-induced PCC in HCT-116 and OVCAR-8 cells. Furthermore, mouse embryonic fibroblasts (MEF) with homozygous deletion in Raf1, but not deletion in the related kinase Braf, were resistant to LSA-induced PCC. Complementation of Raf1−/− MEFs with wild-type human RAF1, but not with kinase-dead RAF1 mutant, restored LSA-induced PCC. Finally, the Raf inhibitor sorafenib, but not the MEK inhibitor AZD6244, effectively suppressed LSA-induced PCC. Our findings implicate a previously unknown, MAPK-independent role of RAF1 in chromatin condensation and potent activation of this pathway by LSA. View Full-Text
Keywords: chromosome condensation; c-raf; lasonolide A; shRNA; myosin phosphatase chromosome condensation; c-raf; lasonolide A; shRNA; myosin phosphatase
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Jossé, R.; Zhang, Y.-W.; Giroux, V.; Ghosh, A.K.; Luo, J.; Pommier, Y. Activation of RAF1 (c-RAF) by the Marine Alkaloid Lasonolide A Induces Rapid Premature Chromosome Condensation. Mar. Drugs 2015, 13, 3625-3639.

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