Zhijun Luo

Associate Professor of Biochemistry
Department of Biochemistry

Zhijun Luo

Boston University School of Medicine
Evans Building
715 Albany Street, E645
Boston, MA. 02118

Phone: 617-414-1033

Email: zluo@bu.edu

Education

Ph.D., Albert Einstein College of Medicine, Yeshiva University, New York.

Research Interest

Regulation of tumor cell growth and metabolism by protein phosphorylation

Ongoing Research Projects

Almost all cellular programs are regulated by phosphorylation, of which an important aspect is the controlling of cell proliferation, survival and apoptosis.  Dysregulation of responsible kinases has often been found to contribute to the unrestrained growth of cancer cells. Thus, the overall research interest of our laboratory is to understand how protein phosphorylation regulates cell proliferation, and how its alteration causes diseases such as cancer and metabolic disorders.  Our current research focuses on the regulation and function of AMP-activated protein kinase and Raf kinase, both of which have been implicated in cancer and other disorders.

  1. AMP-activated protein kinase (AMPK) consists of a α catalytic subunit (α1, α2) and β (β1, β2) and γ(γ1, γ2, γ3) regulatory subunits.  AMPK serves as a fuel-sensing enzyme that is activated by binding of 5′ AMP to the γ subunits, which triggers a conformational change enabling phosphorylation of T172 in the activation loop of the catalytic subunit 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.  Thus, we have demonstrated that sustained activation of AMPK by pharmacological activators attenuates the growth of cancer cells, concomitant with the inhibition of mTOR and FAS and upregulation of p53 and p21, whereas expression of the dominant negative mutant of AMPK causes opposite changes.  We are currently examining whether AMPK activity is suppressed in cancer cells and if so, whether it is associated with altered metabolic states such as increased glycolysis and de novo fatty acid synthesis.  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 in regulation of cancer cell growth.
  2. Raf kinases, consisting of three isoforms, Raf-1, B-Raf and A-Raf, act as immediate downstream effectors of Ras.  The Raf kinases as prototypical kinases belong to the MEKK superfamy that directly phosphorylate and activate the downstream targets MEK1/2 in response to extracellular stimuli.  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.

Representative Publications

  1. Luo ZJ, Zhang X, Rapp U, and Avruch J.  Identification of the 14.3.3 zeta domains important for self association and Raf binding.  J. Biol. Chem. 270: 23681-23687, 1995.
  2. Luo Z*, Tzivion G, Belshaw PJ, Vavvas D, Marshall M, and Avruch J.  Oligomerization activates c-Raf-1 through a Ras-dependent mechanism. Nature 383: 181-185, 1996 [see comments] (*Corresponding author).
  3. Luo Z*, Diaz B, Marshall M, and Avruch J. An intact Raf zinc finger is required for optimal binding to processed Ras, and for Ras-dependent Raf activation in situ. Mol. Cell. Biol. 17: 46-53,1997. (*Corresponding author).
  4. Tzivion G, Luo Z, and Avruch J. A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity. Nature 394: 88-92, 1998.
  5. Hayne C, Tzivion G, and Luo Z. Raf-1/MEK/MAPK pathway is necessary for the G2/M transition induced by nocodazole.  J. Biol. Chem. 275:31876-31882, 2000.
  6. Zang M, Waelde CA, Xiang X, Rana A, Wen Rong, and Luo Z. Activation of Raf-1 by EGF and disrupting microtubule integrity through different mechanisms. J. Biol. Chem. 276: 25157-25165, 2001.
  7. Zang M, Hayne C, and Luo Z. Interaction between active Pak1 and Raf-1 is necessary for phosphorylation and activation of Raf-1. J. Biol. Chem. 277: 4395-4405, 2002.
  8. Xiang X, Yuan M, Ruderman N, and Luo Z. 14-3-3 facilitates insulin-stimulated dissociation of IRS-1 from high speed pellet fraction. Mol. End. 16: 552-562, 2002.
  9. Xu C. W. and Luo Z. Inactivation of Ras function by allele-specific peptide aptamers.  Oncogene 21: 5753-5757, 2002.
  10. Xiang X, Zang M, Waelde CA, Wen R, and Luo Z. Phosphorylation of S338SYY341 regulates specific interaction between Raf-1 and MEK1.  J. Biol. Chem 277: 44996-45003, 2002.
  11. Luo ZG, Wang Q, Zhou JZ, Wang JB, Luo Z, Liu M, He X, Wynshaw-Boris A, Xiong WC, Lu B, and Mei L. Regulation of AchR clustering by Dishevelled interacting with MuSK and Pak1. Neuron. 35: 489-505, 2002.
  12. 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.
  13. Hayne C, Xiang X, Luo Z.  MEK inhibition and phosphorylation of serine 4 on B23 are two coincident events in mitosis.  Biochem. Biophys. Res. Comm. 321: 675-680, 2004.
  14. Luo Z, Saha AK, Xiang X, and Ruderman NB. AMPK, the metabolic syndrome and cancer. TIPS 26: 69-76, 2005.
  15. in Y, Dai M-S, Lu, SZ, Xu Y, Luo Z, Zhao Y, and Lu H.  14-3-3g associates with MDMX that is phosphorylated by UV-activated ChK1, resulting in p53 activation.  EMBO J 25: 1207-18, 2006.
  16. Chadee DN, Hung G, Andalibi A, Lim DJ, Luo Z, Gutmann DH, and Kyriakis KM. MLK3 regulates B-Raf through a mechanism that involves maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein.  Proc. Natl. Acad. Sci. 103: 4463-68, 2006.
  17. Guo W, Wong S, Xie W, Lei T, Luo Z. Palmitate Modulates Intracellular Signaling, Induces Endoplasmic Reticulum Stress, and Causes Apoptosis in Mouse 3T3-L1 and Rat Primary Preadipocytes. Am J Physiol Endocrinol Metab. 293:E576-86, 2007.
  18. Chakrabarti P, Anno T, Manning BD, Luo Z, and Kandror KV. The mTOR complex 1 regulates leptin biosynthesis in adipocytes at the level of translation. The role of the 5′-UTR in the expression of leptin mRNA.  Mol Endol 22: 2260-7, 2008.
  19. 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.
  20. 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.  2009.  In press.
  21. 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. 2009. In press.
Primary teaching affiliate
of BU School of Medicine