Boston University School of Medicine
715 Albany Street, E645
Boston, MA. 02118
PhD, Albert Einstein College of Medicine, Yeshiva University, New York.
Regulation of tumor cell growth and metabolism by protein phosphorylation
The overall research interest in my laboratory is to understand how protein phosphorylation regulates cell growth and metabolism, and how its alteration causes diseases such as cancer and metabolic disorders. Our ongoing research focuses on characterization of AMP-activated protein kinase and Raf kinase, both of which have been implicated in cancer and other disorders.
AMPK serves as a fuel-sensing enzyme that is activated by binding of 5’ AMP to the gamma subunit and phosphorylation of the catalytic subunit at Thr 172 by upstream kinases such as LKB1 and CaMKK. The activation of AMPK has been shown to improve metabolic syndrome and to be implicated in control of cancer cell growth. One of our research interests is to test the hypothesis that AMPK functions as a metabolic tumor suppressor. Using microarray and proteomic approaches, we have identified several target molecules regulated by AMPK and are currently evaluating their functional relationship with AMPK and biological relevance.
Raf kinases, consisting of three isoforms, Raf-1, B-Raf and A-Raf, act as immediate downstream effectors of Ras. They are implicated in tumorigenesis, inasmuch as activating mutations of the ras genes have been found in 20-30% of overall human cancers and activated mutants of B-Raf frequently reported in human cancers. Although the linear relationship of the Ras/Raf/MEK/Erk signaling pathway has been delineated, the mechanism of Raf activation still remains elusive. We have a long standing interest in characterizing phosphorylation of Raf for its activation, and identifying kinases responsible for these phosphorylation events and downstream targets in addition to MEK1/2.
- ATM and LKB1 dependent activation of AMPK sensitizes cancer cells to etoposide-induced apoptosis. Luo L, Huang W, Tao R, Hu N, Xiao ZX, Luo Z. Cancer Lett. 2013 Jan 1;328(1):114-9. doi: 10.1016/j.canlet.2012.08.034. Epub 2012 Sep 5.
- SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL. Chakrabarti P, English T, Karki S, Qiang L, Tao R, Kim J, Luo Z, Farmer SR, Kandror KV. J Lipid Res. 2011 Sep;52(9):1693-701. doi: 10.1194/jlr.M014647. Epub 2011 Jul 8.
- Li Y, Xu S, Mihaylova M, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E,. Shyy J Y-J , Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin resistant Mice. Cell Metabolism. 13:376-88, 2011, PMID:21459323.
- Zhou J, Yang Z, Tsuji T, Gong J, Xie J, Chen C, Li W, Amar S, Luo Z. LITAF and TNFSF15, two downstream targets of AMPK, exert inhibitory effects on tumor growth. Oncogene, 30: 1892-900.2011, PMID: 21217782.
- Tao R, Gong J, Luo X, Zang M, Guo W, Wen R, Luo Z. AMPK exerts dual regulatory effects on the PI3K pathway. J Mol Signal. 5: 1-9. 2010, PMC PMC 2848036.
- Luo Z, Zang M, Guo W. AMP-activated protein kinase – metabolic tumor suppressor: control of metabolism and cell growth. Future Oncology6:457-70, 2010, PMC: 2854547.
- Zhou J, Huang W, Tao R, Ibaragi R, Lan L, Ido Y, Wu X, Alekseyev Y, Lendburg M, Hu G-F, Luo Z. Inactivation of AMPK alters gene expression and promotes growth of prostate cancer cells. Oncogene 28: 1993-2002 2009.
- Ma T, Zhao Y, Kwak YD, Yang Z, Thompson R, Luo Z, Xu H, Liao FF. Statin’s excitoprotection is mediated by sAPP and the subsequent attenuation of calpain-induced truncation events, likely via rho-ROCK signaling.J Neurosci.29:11226-36, 2009
- Chen Y, Wang R, Kun Z, Kwak Y-D, Liu Y, Ma T, Thompson RC, Zhao YB, Gasparini L, Luo Z, Xu H, Liao F-F. Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via upregulating BACE1 transcription. Proc. Natl. Acad. Sci.106:3907-12, 2009.
- Zang M, Gong J, Luo L, Zhou J Xiang X, Huang W, Huang Q, Luo X, Olbrot M, Peng Y, Chen C, Luo Z. Characterization of S338 phosphorylation in Raf-1 activation. J Biol Chem,283: 31429-37, 2008.
- Luo Z, Saha AK, Xiang X, and Ruderman NB. AMPK, the metabolic syndrome and cancer. TIPS26: 69-76, 2005.
- Xiang X, Saha AK, Wen R, Ruderman NB, and Luo Z. AMP-activated protein kinase activators can inhibit the growth of prostate cancer cells by multiple mechanisms. Biochem Biophys Res Commun.321: 161-167, 2004.