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Faculty Timothy Hla
Professor of Cell Biology
Director, Center for Vascular Biology
hla@nso2.uchc.edu
Areas of Interest:
Research in Dr. Hla's laboratory is focused on the molecular
mechanisms of angiogenesis, also known as new blood vessel formation.
Angiogenesis is important in physiological events such as wound healing
as well as in pathological conditions such as solid tumor growth and
rheumatoid arthritis. This laboratory has cloned and characterized
several immediate-early genes induced during in vitro
angiogenesis; the inducible cyclooxygenase enzyme Cox-2 and the
G-protein-coupled receptor EDG-1.
Overexpression of Cox-2 is observed in colon cancer, breast cancer
and the angiogenic chronic inflammatory disease of rheumatoid arthritis.
Currently, molecular mechanisms involved in Cox-2 regulation and
function are investigated. We are investigating post-transcriptional
mechanisms that allow exaggerated Cox-2 expression, in situations such
as in breast cancer. In addition, we are overexpressing Cox-2 in
transgenic mice to study the role of this pathway in tumorigenesis and
angiogenesis.
EDG-1 binds to its high affintiy ligand sphingosine-1-phosphate, a
platelet-derived lipid, and regulates the small GTPase Rho- and Rac-dependent
signal transduction events which culminates in morphogenesis, migration,
survival and proliferation of endothelial cells. Indeed, this system
regulates angiogenesis in vivo and is required for embryonic
vascular maturation. Currently, we are working on systems to better
understand how sphingosine 1-phosphate is secreted and how it signals
via the EDG family of G-protein-coupled receptors to regulate
angiogenesis.
Lab Rotation Peojects:
Sphingosine 1-phosphate (S1P) is a lipid mediator that signals via cell
surface G protein-coupled receptors. We showed that S1P signaling is
important in multiple physiological processes, including, angiogenesis,
vascular maturation and embryonic development. We are currently
dissecting the mechanisms of how S1P regulates tumor development in
mouse models. We also investigate the cell biology of S1P signaling via
its receptors and metabolic enzymes.
Another major project in the lab deals with the regulation of
cyclcooxyenase (COX)-2 expression and function. We have identified
post-transcriptional mRNA stabilization as a major event in the
regulation of this gene. In particular, an RNA binding protein, HuR was
shown to be critical. We are currently developing genetic models in mice
to study the significance of post-transcriptional regulation in COX-2
expression and also animal development and diseases such as cancer. When
overexpressed, COX-2 promotes tumor progression. We are utilizing
molecular methods, genetic models and proteomics to study how COX-2
promotes cancer.
Recent Selected Publications:
Sanchez T, Thangada S, Wu MT, Kontos CD, Wu D, Wu H, Hla T. PTEN as
an effector in the signaling of antimigratory G protein-coupled
receptor. Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4312-7. Epub
2005 Mar 11.
Chae SS, Paik JH, Furneaux H, Hla T. Requirement for sphingosine
1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA
interference. J Clin Invest. 2004 Oct;114(8):1082-9.
Paik JH, Skoura A, Chae SS, Cowan AE, Han DK, Proia RL, Hla T.
Sphingosine 1-phosphate receptor regulation of N-cadherin mediates
vascular stabilization. Genes Dev. 2004 Oct 1;18(19):2392-403. Epub 2004
Sep 15.
Brinkmann V, Cyster JG, Hla T. FTY720: sphingosine 1-phosphate
receptor-1 in the control of lymphocyte egress and endothelial barrier
function. Am J Transplant. 2004 Jul;4(7):1019-25. Review.
Chae SS, Paik JH, Allende ML, Proia RL, Hla T. Regulation of limb
development by the sphingosine 1-phosphate receptor S1p1/EDG-1 occurs
via the hypoxia/VEGF axis. Dev Biol. 2004 Apr 15;268(2):441-7.
Chang SH, Liu CH, Conway R, Han DK, Nithipatikom K, Trifan OC, Lane
TF, Hla T. (2004) Role of prostaglandin E2-dependent angiogenic
switch in cyclooxygenase 2-induced breast cancer progression Proc
Natl Acad Sci U S A. 2004 Jan 13; 101(2): 591-6.
Sanchez T, Estrada-Hernandez T, Paik JH, Wu MT, Venkataraman K,
Brinkmann V, Claffey K, Hla T. (2003) Phosphorylation and action of
the immunomodulator FTY720 inhibits VEGF-induced vascular permeability.
J Biol Chem. 2003 Sep 3
Sengupta S, Jang BC, Wu MT, Paik JH, Furneaux H, Hla T. (2003) The
RNA-binding protein HuR regulates the expression of cyclooxygenase-2.
J Biol Chem. 278:25227-33.
Jang BC, Munoz-Najar U, Paik JH, Claffey K, Yoshida M, Hla T. (2003)
Leptomycin B, an inhibitor of the nuclear export receptor CRM1,
inhibits COX-2 expression. J Biol Chem. 278:2773-6.
Bishop-Bailey D, Hla T, Warner TD. (2002) Intimal smooth muscle
cells as a target for peroxisome proliferator-activated receptor-gamma
ligand therapy Circ Res. 91:210-7.
Chun J, Goetzl EJ, Hla T, Igarashi Y, Lynch KR, Moolenaar W, Pyne S,
Tigyi G. (2002) International Union of Pharmacology. XXXIV.
Lysophospholipid receptor nomenclature. Pharmacol Rev. 54:265-9.
Ancellin N, Colmont C, Su J, Li Q, Mittereder N, Chae SS, Stefansson
S, Liau G, Hla T. (2002) Extracellular export of sphingosine kinase-1
enzyme. Sphingosine 1-phosphate generation and the induction of
angiogenic vascular maturation. J Biol Chem. 277:6667-75.
Hla, T., Lee, M.-J., Ancellin, N., Paik, J. H., Kluk, M.J. (2001)
Lysophospholipids -- receptor revelations. CScience 294, 1875-1878
Lee, M-J., Thangada, S., Paik, JH, Sapkota, GP, Ruiz, MM, Ancellin,
N, Wu, M-T, Sessa, WC, Alessi, D, and Hla, T. (2001) Akt mediated
phosphorylation of the G-protein-coupled receptor EDG-1 is required for
endothelial cell chemotaxis. Mol. Cell. 8, 693-704.
Liu, C. H., Chang, Sung-Hee, Trifan, O. C., Narko, K., Smith, E.,
Haudenschild, C., Lane, T. F. and Hla, T. (2001) Over-expression of
cyclooxygenase (Cox)-2 gene is sufficient to induce tumorigenesis in
transgenic mice. J. Biol. Chem. 276, 18563-18569.
Paik, Ji H, Chae, Sungsuk, Lee, Menq-Jer, Thangada, Shobha and Hla,
T. (2001) Serum withdrawal-induced post-transcriptional stabilization
of cyclooxygenase (COX)-2 mRNA in MDA-MB-231 mammary carcinoma cells
requires the activity of the p38 stress-activated protein (SAP) kinase.
J. Biol. Chem. 275, 39507-39515. |
