 |
FRISC: The Faculty Research Interests Science Comparator |
|
Assistant Professor of Internal Medicine
Cell
Regulation
Office: 214-648-1837
FAX: 214-648-4940
Email: preet.chaudhary@utsouthwestern.edu
Our main area of research interest is signal transduction
by the members of the Tumor Necrosis Factor Receptor (TNFR) Family. Different
members of this family have been shown to play a crucial role in the regulation
of cellular proliferation, activation and programmed cell death. We have
recently isolated several novel members of this family and characterized the
signal transduction pathways utilized by them. Our work on the signal
transduction pathway utilized by Death Receptor 5 (DR5/TRAIL-R2), a receptor for
the cytotoxic ligand TRAIL ( Immunity,
1997, 7 (6) 821-830), characterized the adaptor molecules involved in the signal
transduction by DR5. Furthermore, it clarified major misconceptions about
the signal transduction pathway utilized by another TRAIL receptor, designated
DR4 or TRAIL Receptor 1.
A related project in our laboratory is the investigation of
cross-communication among the different signal transduction pathways initiated
upon the activation of the TNFR family members. For example, signaling via
TNFR1, the best characterized member of this family, is believed to lead to
activation of two major pathways: a caspase cascade leading to cell death and a
kinase cascade leading to the activation of the NF- k B
and JNK pathways. These two pathways are believed to diverge at the level of an
adaptor molecule TRADD (TNFR1 Associated Death Domain). We have recently
discovered a novel pathway by which Caspase 8 (or FLICE), the apical caspase of
the caspase cascade, can activate the NF- k B and JNK
pathways, which suggests the existence of a cross-talk between the caspase and
kinase cascades downstream of TRADD. We have localized the NF- k B
and JNK activating regions of Caspase 8 to its prodomain, which contains two
homologous “Death Effector Domains”. These results suggest that Caspase 8
may have functions beyond its activity as a pro-apoptotic protease. We are
currently investigating the molecular mechanism of Caspase 8-induced NF- k B
and JNK activation and its physiological role in signal transduction by
different members of the TNFR family using a transgenic approach.
We have also discovered that orf-K13, a Death Effector
Domains-containing protein (also called vFLIP or viral FLICE inhibitory protein)
encoded by the Kaposi’s Sarcoma associated Herpes Virus (KSHV), is also
capable of activating the NF- k B pathway, while
simultaneously blocking cell death induced by TNFR1 and other death-inducing
receptors. As orf-K13 is one of the few KSHV encoded proteins that are
expressed in latently infected Kaposi’s Sarcoma spindle and primary effusion
lymphoma (PEL) cells, we believe that it is good candidate for mediating the
cellular transformation seen in association with infection by this virus. We are
currently testing this hypothesis using in
vitro and in vivo approaches.
We also isolated TAJ, another member of the TNFR family. We recently
described the ability of this receptor to activate the JNK pathway and to
mediate cell death by a caspase-independent mechanism. We are currently
attempting a better understanding of signaling via TAJ using a combination of
molecular and biochemical techniques. TAJ is mainly expressed in
developing skin, hair follicles and adult prostate. Therefore, we are currently
testing the expression of TAJ in various forms of skin and prostate cancer with
the hope of exploiting its cell killing ability for the treatment of these
diseases. In addition, TAJ appears to play a major role in hair growth and
development, and may provide a novel therapeutic approach to the treatment of
hair loss seen following chemotherapy.
Selected Publications:
Chaudhary, P.M., Eby, M., Jasmin,
A., Kumar, A., Liu, L., and Hood, L. (2000). Activation of the NF- k B
pathway by Caspase 8 and its homologs. Oncogene .
In press.
Eby, M.T., Jasmin, A., Kumar,
A., Sharma, K., and Chaudhary, P.M. (2000). TAJ, a novel member of the Tumor
Necrosis Factor Receptor family, activates the c-Jun N-terminal Kinase pathway
and mediates caspase-independent cell death. J. Biol Chem . 275 (20), 15336-15342.
Chaudhary, P.M., Eby, M., Jasmin,
A., and Hood, L. (1999). Activation of the JNK/SAPK pathway by Caspase 8 and its
homologs . J. Biol Chem. 274 (27),
19211-19219.
Chaudhary, P.M., Eby, M., Jasmin,
A., Gimmell, A and Hood, L. (1999). Modulation of the NF- k B
pathway by virally encoded Death Effector Domains-containing proteins. Oncogene .
18(42):5738-46.
Yun, T.J., Chaudhary, P.M., Shu,
G.L., Frazer, J.K., Ewings, M.K., Schwartz, S., Pasqual, V., Hood, L., and
Clark, E.A. (1998). OPG/FDCR-1, a TNFR family member, is expressed in lymphoid
cells and is upregulated by ligating CD40. J.
Immunol . 161(11) 6113-6121.
Chaudhary, P.M.,* Han, D.K.,*
Wright, M.E., Friedman, C., Trask, B.J., Riedel R.T., Baskin, D.G., Schwartz,
S.M., and Hood, L. (1997). MRIT, a novel death-effector domain-containing
protein, interacts with caspases and BclXL and initiates cell death. Proc
Natl Acad Sci USA 1 4, 94(21):1133311338. * Co-first authors.
Chaudhary, P.M., Eby, M., Jasmin, A., Bookwalter, A., Murray, J., and Hood, L.
(1997). Death Receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent
apoptosis and activate the NF- k B pathway. Immunity
7 (6) 821-830.
Extraction Method: Expand using Medical Synonyms-
Eliminated words list: MedlinePlus List
-
Similarity Method: Weighted keyword count
-
Database: Medline abstracts (1967 - Present)
-
Publication Type: All
-
Score Calculation Method: Cosine Similarity Method
-
Sort by: Score
-
Show: Top 100 hits
-
Results computed on: 6/9/2006