{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T17:14:15Z","timestamp":1764782055633,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2015,6,5]],"date-time":"2015-06-05T00:00:00Z","timestamp":1433462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>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\u2019s 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\u2212\/\u2212 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.<\/jats:p>","DOI":"10.3390\/md13063625","type":"journal-article","created":{"date-parts":[[2015,6,5]],"date-time":"2015-06-05T10:23:07Z","timestamp":1433499787000},"page":"3625-3639","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Activation of RAF1 (c-RAF) by the Marine Alkaloid Lasonolide A Induces Rapid Premature Chromosome Condensation"],"prefix":"10.3390","volume":"13","author":[{"given":"Rozenn","family":"Joss\u00e9","sequence":"first","affiliation":[{"name":"Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute (CCR-NCI), NIH, Bethesda, MD 20892-9760, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong-Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute (CCR-NCI), NIH, Bethesda, MD 20892-9760, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentin","family":"Giroux","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute (CCR-NCI), NIH, Bethesda, MD 20892-9760, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arun","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Departments of Chemistry and Medicinal Chemistry, Purdue University; West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji","family":"Luo","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute (CCR-NCI), NIH, Bethesda, MD 20892-9760, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yves","family":"Pommier","sequence":"additional","affiliation":[{"name":"Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute (CCR-NCI), NIH, Bethesda, MD 20892-9760, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2015,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"363","DOI":"10.2174\/1568011043352939","article-title":"Lamellarins, from A to Z: A family of anticancer marine pyrrole alkaloids","volume":"4","author":"Bailly","year":"2004","journal-title":"Curr. 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