GEORGE P. STUDZINSKI
1958 University of Glasgow
of differentiation of human leukemic cells by novel analogs
Signaling of differentiation of human leukemia cells
With the ultimate goal of improving the prevention and treatment of human myeloid leukemias, we are investigating the molecular mechanisms that reverse the malignant behavior of leukemia cells. This is primarily done using established leukemia cell lines, which can be normalized by an exposure to several agents including the physiologically active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25D 3 ). We have previously shown that differentiation of human leukemia cells HL60 results in a proliferative block that is due to the upregulation of the expression of the Cdk inhibitor p27 Kip1. Current studies focus on the mechanisms by which this upregulation takes place, and the relationship of signaling by mitogen-activated protein kinases (MAPKs) to differentation and cell cycle arrest. The mechanisms include the upregulation of the retinoblastoma susceptibility protein (pRb), and its interaction with transcription factors such as C/EBPß. Additional studies focus on the reversal of resistance of leukemia cells to 1,25D 3 , and its less calcemic analogs by plant antioxidants.
To increase the translational value of our studies we have established collaborations with clinicians who provide leukemic blood samples (following informed consent of the patients) for parallel studies ex vivo .
Studzinski, G.P. “Cell differentiation in vitro; model systems” in: Encyclopedia of Life Sciences, MacMillan Press, London, 2001.
Studzinski, G.P. A Compact Compendium on Caspases. Cell Cycle, 2:160-161, 2003.
Studzinski, P.G., Harrison, J.S. The neuronal cyclin-dependent kinase 5 activator p35Nck5a and Cdk5 activity in monocytic cells. Leukemia and Lymphoma, 44:235-240, 2003.
Danilenko, M., Wang, Q., Wang, X., Levy, J., Sharoni, Y., Studzinski, G.P. Carnosic acid potentiates the antioxidant and prodifferentiation effects of 1a,25-dihydroxyvitamin D 3 in leukemia cells, but does not promote elevation of basal levels of intracellular calcium. Cancer Res., 63:1325-1332, 2003.
Wang, Q., Wang, X., Studzinski, G.P. The jun N-terminal kinase pathway enhances signaling of monocytic differentiation of human leukemia cells induced by 1,25-dihydroxyvitamin D 3 . J. Cellular Biochem., 89:1087-1101, 2003.
Wang, X., and Studzinski G.P. Kinase suppressor of RAS (KSR) amplifies the differentiation signal provided by low concentrations 1,25-dihydroxyvitamin D 3. J. Cellular Physiology, 198:333-342, 2004.
Weyts, F.A., Dhawan, P., Zhang, X., Bishop, J.E., Uskokovic, M.R., Ji, Y., Studzinski, G.P., Norman, A.W., and Christakos, S. Novel Gemini analogs of 1,25-dihydroxyvitamin D 3 with enhanced transcriptional activity. Biochem. Pharmacol., 67:1327-1336, 2004.
Ji, Y., and Studzinski, G.P. Retinoblastoma Protein and CCAAT/Enhancer-binding protein ß are required for 1,25-dihydroxyvitamin D 3 -induced differentiation of HL60 Cells. Cancer Res,. 64:370-377, 2004.
Chen, F., Wang, Q., Wang, X., and Studzinski, G.P. Upregulation of Egr1 by 1,25-dihydroxyvitamin D 3 contributes to increased expression of p35 activator of Cdk5 and consequent onset of the terminal phase of HL60 cell differentiation. Cancer Res., In press, 2004.