Manabu Kurokawa, Ph.D.
Assistant Professor of Pharmacology & Toxicology
Pharmacology & Toxicology
University of Massachusetts, Amherst – Ph.D. 2004
Hokkaido University – DVM 1999
Program in Experimental and Molecular Medicine
HB 7650, Pharmacology & Toxicology
Geisel School of Medicine
Hanover NH 03755
Dr. Kurokawa’s research interests lie in the fields of programmed cell death and cancer. Chemotherapeutic agents typically function by triggering a cell death program known as apoptosis, which promotes the release of cytochrome c from the mitochondria into the cytoplasm and stimulates activation of cell-death proteases, caspases, through formation of a complex called the apoptosome. However, cancer cells are often able to acquire resistance to these drugs and evade death by somehow blocking mitochondrial cytochrome c release and/or inhibiting caspase activation. Dr. Kurokawa’s laboratory employs a panel of cancer cell lines which are resistant to specific anti-cancer agents, to include kinase inhibitors, as a model system to gain more insight into the molecular mechanism(s) underlying acquired resistance. These cell lines have been isolated by continuous culture in the presence of the drugs at clinically relevant therapeutic concentrations. This approach mimics the relevant clinical setting where patients receive the chemotherapeutic agent on a daily basis. Using the resistant cell lines as tools, the laboratory systematically dissects the apoptotic signaling pathways both upstream and downstream of the mitochondria to identify the specific alterations that render cancer cells unresponsive to drug treatment and aims to elucidate the apoptotic signaling pathways most critical for the development and maintenance of acquired chemoresistance. One of the laboratory’s current research focuses is to elucidate the molecular mechanisms of acquired resistance to the FDA-approved HER2 inhibitor lapatinib in HER2-positive breast cancer cells.
Rotations and Thesis Projects:
Various small and large projects are available in the Kurokawa lab, which include:
1) Establish and analyze cell line and mouse models of acquired drug resistance in breast cancer and melanoma.
2) Molecular dissection of apoptotic signaling pathways in a panel of cancer cell lines before and after specific anti-cancer agents
3) The regulation of the E3 ligase HUWE1 in cancer
NIH NCI R00 CA140948
Dr. Kurokawa, a native of Japan, received a Bachelor of Veterinary Medicine (equivalent to the D.V.M. in the United States) from Hokkaido University in 1999. He moved to the United States to pursue doctoral work at the University of Massachusetts Amherst, studying the basic signaling mechanisms of fertilization under the supervision of Dr. Rafael Fissore. He received his Ph.D. in 2004. Dr. Kurokawa conducted his postdoctoral research in the laboratory of Dr. Sally Kornbluth at Duke University, studying the regulation of apoptosis in cancer. In 2012, Dr. Kurokawa joined the faculty in the Department of Pharmacology and Toxicology at the Geisel School of Medicine at Dartmouth as an Assistant Professor.
Kurokawa M, Yoon SY, Alfandari D, Fukami K, Sato K, Fissore RA. Proteolytic processing of phospholipase Czeta and [Ca2+]i oscillations during mammalian fertilization. Dev Biol. 2007 Dec;312(1):407-18. (view details on MedLine)
Kurokawa M, Zhao C, Reya T, Kornbluth S. Inhibition of apoptosome formation by suppression of Hsp90beta phosphorylation in tyrosine kinase-induced leukemias. Mol Cell Biol. 2008 Sep;28(17):5494-506. (view details on MedLine)
Nutt LK, Buchakjian MR, Gan E, Darbandi R, Yoon SY, Wu JQ, Miyamoto YJ, Gibbons JA, Andersen JL, Freel CD, Tang W, He C, Kurokawa M, Wang Y, Margolis SS, Fissore RA, Kornbluth S. Metabolic control of oocyte apoptosis mediated by 14-3-3zeta-regulated dephosphorylation of caspase-2. Dev Cell. 2009 Jun;16(6):856-66. Erratum in: Dev Cell. 2010 Jan;18(1):165. (view details on MedLine)
Kurokawa M, Kornbluth S. Caspases and kinases in a death grip. Cell. 2009 Sep;138(5):838-54. Review. (view details on MedLine)
Kurokawa M, Kornbluth S. Stalling in mitosis and releasing the apoptotic brake. EMBO J. 2010 Jul;29(14):2255-7. (view details on MedLine)
Kim J, Parrish AB, Kurokawa M, Matsuura K, Freel CD, Andersen JL, Johnson CE, Kornbluth S. Rsk-mediated phosphorylation and 14-3-3ɛ binding of Apaf-1 suppresses cytochrome c-induced apoptosis. EMBO J. 2012 Jan;31(5):1279-92. doi: 10.1038/emboj.2011.491. (view details on MedLine)
Kurokawa M, Ito T, Yang CS, Zhao C, Macintyre AN, Rizzieri DA, Rathmell JC, Deininger MW, Reya T, Kornbluth S. Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells. Proc Natl Acad Sci U S A. 2013 Fe;110(6):2300-5. (view details on MedLine)
Kurokawa M, Kim J, Geradts J, Matsuura K, Liu L, Ran X, Xia W, Ribar TJ, Henao R, Dewhirst MW, Kim WJ, Lucas JE, Wang S, Spector NL, Kornbluth S. A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53. Sci Signal. 2013 May;6(274):ra32. (view details on MedLine)
McCoy F, Darbandi R, Lee HC, Bharatham K, Moldoveanu T, Grace CR, Dodd K, Lin W, Chen SI, Tangallapally RP, Kurokawa M, Lee RE, Shelat AA, Chen T, Green DR, Harris RA, Lin SH, Fissore RA, Colbran RJ, Nutt LK. Metabolic activation of CaMKII by coenzyme A. Mol Cell. 2013 Nov;52(3):325-39. (view details on MedLine)
Fernald K, Kurokawa M. Evading apoptosis in cancer. Trends Cell Biol. 2013 Dec;23(12):620-33. (view details on MedLine)