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 Projects
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.
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.
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