James Brugarolas, M.D., Ph.D.

M.D., University of Navarra Medical School, Spain - 1993
Ph.D, Massachusetts Institute of Technology – 1998
Virginia Murchison Linthicum Endowed Scholar in Biomedical Research, UT Southwestern Medical Center
Assistant Professor, Departments of Developmental Biology, Hematology-Oncology and Simmons Comprehensive Cancer Center

GENETICS AND DEVELOPMENT
CANCER BIOLOGY

Office: (214) 648-4059
FAX: (214) 648-1960
Building NB, Room 5.102A
E-mail: james.brugarolas@UTSouthwestern.edu
Brugarolas Lab Webpage

Research Interests:

Our lab is interested in Renal Cell Carcinoma (RCC). We focus both on the basic science aspects of RCC development as well as on research translation.

RCC affects about 35,000 individuals in the US every year. Clear Cell RCC is the most frequent histological type and it usually arises as a result of mutations in the VHL tumor suppressor gene. pVHL functions normally in an oxygen sensing pathway. pVHL degrades the Hypoxia-inducible factor (HIF) transcription factor when oxygen is present. It is very intriguing that a protein that normally functions in oxygen sensing, when mutated, predisposes to tumor development.

Based on some similarities between two highly divergent tumor prone syndromes, von Hippel-Lindau (resulting from germline mutation in VHL) and Tuberous Sclerosis Complex (resulting from germline mutation in either TSC1 or TSC2), we hypothesized that HIF might also be regulated by TSC1/TSC2. The TSC1 and TSC2 proteins form a protein complex and we have now demonstrated that they also regulate HIF. Understanding the mechanism whereby TSC1/TSC2 regulates HIF and the role of HIF in tumor development in Tuberous Sclerosis Complex patients are areas of intense research in the lab.

We have further discovered that the TSC1/TSC2 complex is also in a pathway regulated by oxygen. In response to hypoxia, translation initiation is inhibited, and this process requires TSC1/TSC2. While the mechanism whereby hypoxia regulates TSC1/TSC2 remains to be elucidated, we have identified a critical component of this signaling pathway, the REDD1 protein. Using both loss-of-function as well as gain-of-function studies we have determined that REDD1 is both necessary and sufficient for hypoxia signaling. Biochemical and genetic studies incorporating innovative technologies are underway to determine how REDD1 functions.

Finally, the lab is embarking upon an ambitious project in RCC translational medicine. The objectives of this project are threefold. First, the discovery of new pathways leading to RCC development using a variety of genomic and bioinformatic tools. Second, the evaluation of these pathways as potential targets for new therapies. Third, the development of in vitro systems with therapeutic predictive value.

The identification and careful analysis of biochemical pathways involved in RCC development should lay a fertile ground for the development of new and more effective therapies for patients with this disease.

Awards & Honors:

Claudia Adams Barr Award for Innovative Basic Cancer Research, Dana-Farber Cancer Institute, Harvard Medical School (2003)

Young Investigator Award, Brigham and Women’s Hospital Department of Medicine, Harvard Medical School (2004)

Virginia Murchison Linthicum Endowed Scholar in Biomedical Research, UT Southwestern Medical Center(2006)

Selected References:

Brugarolas, J ., C. Chandrasekaran, J.I. Gordon, D. Beach, T. Jacks, and G.J. Hannon. 1995. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377: 552-7.

Attardi, L.D., S.W. Lowe, J. Brugarolas , and T. Jacks. 1996. Transcriptional activation by p53, but not induction of the p21 gene, is essential for oncogene-mediated apoptosis. Embo J 15: 3693-701.

Montes de Oca Luna, R., L.L. Amelse, A. Chavez-Reyes, S.C. Evans, J. Brugarolas , T. Jacks, and G. Lozano. 1997. Deletion of p21 cannot substitute for p53 loss in rescue of mdm2 null lethality. Nat Genet 16: 336-7.

Brugarolas, J. and T. Jacks. 1997. Double indemnity: p53, BRCA and cancer. Nat Med 3: 721-2.

Brugarolas, J., R.T. Bronson, and T. Jacks. 1998. p21 is a critical CDK2 regulator essential for proliferation control in Rb-deficient cells. J Cell Biol 141: 503-14.

Xu, Y., E.M. Yang, J. Brugarolas , T. Jacks, and D. Baltimore. 1998. Involvement of p53 and p21 in cellular defects and tumorigenesis in Atm-/- mice. Mol Cell Biol 18: 4385-90.

Brugarolas, J ., K. Moberg, S.D. Boyd, Y. Taya, T. Jacks, and J.A. Lees. 1999. Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma-irradiation. Proc Natl Acad Sci U S A 96: 1002-7.

Brugarolas, J., B.F. Haynes, and J.R. Nevins. 2001. Towards a genomic-based diagnosis. Lancet 357: 249-50

Brugarolas, J., J.W. Clark, and B. Chabner. 2003. Using "rationally designed drugs" rationally. Lancet 361: 1758-9.

Brugarolas, J.B ., F. Vazquez, A. Reddy, W.R. Sellers, and W.G. Kaelin, Jr. 2003. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4: 147-58.

Majumder, P.K., P.G. Febbo, R. Bikoff, R. Berger, Q. Xue, L.M. McMahon,J. Manola,   J. Brugarolas , T.J. McDonnell, T.R. Golub, M. Loda, H.A. Lane, and W.R. Sellers. 2004. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10: 594-601.

Brugarolas, J . and W.G. Kaelin, Jr. 2004. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 6: 7-10.

Brugarolas, J., K. Lei, R.L. Hurley, B.D. Manning, J.H. Reiling, E. Hafen, L.A. Witters, L.W. Ellisen, and W.G. Kaelin, Jr. 2004. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18: 2893-904.

T o access any of the publications referenced on this website please visit http://www.ncbi.nlm.nih.gov/PubMed