Faculty and Staff Directory
Research Concentration - Biology of Cellular Stress
College of Arts and Sciences
|Office:||CLS, Room 505|
Our research focuses on regulation of cell survival and apoptosis by interferon-induced, double-stranded RNA activated protein kinase PKR. In particular, we study the regulation of PKR’s kinase activity by its activator protein PACT (DYT16) in response to stress signals that include oxidative stress, growth factor withdrawal, and endoplasmic reticulum (ER) stress. Our work has major implications on origin, progression, and treatment of many human diseases and disorders such as cancer, neurodegeneration, diabetes, and aging.
Stress signals lead to an increased association of PACT with PKR that causes PKR to become enzymatically active and phosphorylate protein synthesis initiation factor eIF2 alpha. This leads to a general block in protein synthesis and since the amounts of eIF2 alpha in the cell are limiting, even minor changes in eIF2 alpha phosphorylation lead to a significant inhibition of protein synthesis.
We are interested in mechanistic questions that address regulation of cell fate (survival or apoptosis) in response to stress signals. The lab focuses on protein-protein interactions and we use many biochemical and genetic assays to determine how interactions between proteins change in response to environment, primarily by changes in protein modifications such as phosphorylation.
Point mutations in PACT have been shown to lead to early onset, generalized dystonia. We are working towards understanding if the identified substitution mutations in PACT that lead to dystonia change the cellular response to stress and alter the cellular outcome in terms of survival and apoptosis.
In addition to this, in collaboration with the Dudycha lab, we are currently investigating stress response and its effects on aging and longevity using the microcrustacean Daphnia as a model system. We focus on heat shock response, eIF2 alpha phosphorylation, and its relationship to life span determination.
Burnett, S. B., Vaughn, L. S., Strom, J. M., Francois, A., and Patel, R. C. 2019. A truncated PACT protein resulting from a frameshift mutation reported in movement disorder DYT16 triggers caspase activation and apoptosis. J. Cell. Biochem. 120 (1), 19004-19018. doi: 10.1002/jcb.29223.
Chukwurah, E., Patel, R. C. 2018. Stress-induced TRBP phosphorylation enhances its interaction with PKR to regulate cellular survival. Sci. Rep. 8 (1), 1020.
Chukwurah, E., Willingham, V., Singh, M., Castillo-Azofeifa, D., Patel, R. C. 2017. Contribution of the two dsRBM motifs to the double-stranded RNA binding and protein-protein interactions of PACT. J. Cell. Biochem. Dec 12. doi: 10.1002/jcb.26561.
Chukwurah, E., Handy, I., Patel, R. C. 2017. ADAR1 and PACT contribute to efficient translation of transcripts containing HIV-1 trans-activating response (TAR) element. Biochem. J. 474 (7), 1241-1257. PMID: 28167698 DOI: 10.1042/BCJ20160964.
Schumpert, C. A., Anderson, C., Dudycha, J. L., Patel, R. C. 2016. Involvement of Daphnia Sir2 in regulating stress response and lifespan. Aging (Albany, NY). 8 (2), 402-417. PMID: 26978617
Schumpert, C. A., Dudycha, J. L., Patel, R. C. 2015. Development of an efficient RNA interference method by feeding for the microcrustacean Daphnia. BMC Biotechnol. 15(1):91-103. doi: 10.1186/s12896-015-0209-x.
Vaughn, L. S., Bragg, D. C., Sharma, N., Camargos, S., Cardoso, F., and Patel, R.C. 2015. Altered activation of protein kinase PKR and enhanced apoptosis in dystonia cells carrying a mutation in PKR activator PACT. J. Biol. Chem., 290 (37), 22543-22557. doi:10.1074/jbc.M115.669408.
Schumpert, C., Nelson, J., Dudycha, J. L., Patel, R. C. 2015. Telomerase activity and telomere length in Daphnia. PLoS One May 11, 10(5):e0127196. doi: 10.1371/journal.pone.0127196. eCollection 2015.
Schumpert, C., Handy, I., Dudycha, J. L., Patel, R. C. 2014. Relationship between heat shock protein 70 expression and life span in Daphnia. Mechanisms of Ageing and Development, 139, 1-10.
Vaughn, L. S., Snee, B., Patel, R. C. 2014. Inhibition of PKR protects against tunicamycin-induced apoptosis in neuroblastoma cells. Gene, 536, 90-96.
Clerzius G., Shaw E., Daher A., Burugu S., Gélinas J-F., Ear T., Sinck L., Routy J-P., Mouland J. A., Patel R. C., Gatignol A. 2013. The PKR activator, PACT, becomes a PKR inhibitor during HIV-1 replication. Retrovirology, 10, 96.
Handy, I., and Patel, R. C. 2013. STAT1 requirement for PKR-induced cell cycle arrest in vascular smooth muscle cells in response to heparin. Gene, 524, 15-21.
Mittelstadt, M. L., and Patel, R. C. 2012. AP-1 Mediated Transcriptional Repression of Matrix Metalloproteinase-9 by Recruitment of Histone Deacetylase 1 in Response to Interferon β. PLoS One, 7 (8). e42152.
Singh, M. and Patel R. C. 2012. Increased interaction between PACT molecules in response to stress signals is required for PKR activation.J. Cellular Biochemistry, 113 (8). 2754-2764.
Singh M., Castillo D, Patel C. V., and Patel R. C. 2011. Stress-induced phosphorylation of PACT reduces its interaction with TRBP and leads to PKR. Biochemistry, 50. 4550-4560.
Singh, M., Fowlkes, V., Handy, I., Patel, C. V., Patel, R. C. 2009. Essential Role of PACT-mediated PKR activation in tunicamycin-induced apoptosis. J. Mol. Biol., 385. 457-468.
Daher, A., Laraki, G., Singh, M., Melendez-Pena, C. E., Bannwarth, S., Peters, A. H., Meurs, E. F., Braun, R. E., Patel, R. C., Gatignol, A .2009. TRBP control of PACT-induced phosphorylation of PKR is reversed by stress. Mol. Cell. Biol., 29. 254-265.
Trivedi, C. M., Patel, R. C., and Patel, C. V. 2008. Differential regulation of HOXA9 Expression by Nuclear Factor kappa B and HOXA9. Gene, 408. 187.195.
Mittelstadt, M., Frump, A., Khuu, T., Fowlkes, V., Handy, I. Patel, C. V., and Patel, R. C. 2008. Interaction of Human tRNA-dihydrouridine synthase-2 with Interferon-induced Protein Kinase PKR. Nucleic Acids Research, 36. 998-1008.
Trivedi, C. M., Patel, R. C., and Patel, C. V. 2007. Homeobox Gene HOXA9 Inhibits Nuclear Factor - kappa B Dependent Activation of Endothelium. Atherosclerosis, 195. 50-60.
Fasciano, S., Kaufman, A., and Patel, R. C. 2007. Expression of PACT is regulated by Sp1 transcription factor. Gene, 388. 74-82.
Fasciano, S., Hutchins, B., Handy, I., and Patel, R. C. 2005. Identification of PKR’s heparin binding domain and its functional importance in regulation of PKR activity in vascular smooth muscle cells.. FEBS Journal, 272. 1425-1439.
Fasciano, S., Patel, R. C., Handy, I. and Patel C. V. 2005. Regulation of vascular smooth muscle proliferation by heparin: Inhibition of cyclin-dependent kinase activity by p27kip1. J. Biol. Chem., 280. 15682-15689.
Gupta, V., Huang, X., and Patel, R. C. 2003. The carboxy-terminal, M3 motifs of PACT and TRBP have opposite effects on PKR activity.Virology, 351. 283-291.
Patel, R. C., Handy, I., Patel, C. V. 2002. Contribution of double-stranded RNA-activated protein kinase toward antiproliferative actions of heparin on vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol., 221. 1439-1444.
Huang, X., Hutchins, B., and Patel, R. C. 2002. The carboxy-terminal, third conserved motif of the protein activator PACT plays an essential role in the activation of double-stranded-RNA-dependent protein kinase (PKR). Biochem. J., 366. 175-186.
Gupta, V., and Patel, R. C. 2002. Proapoptotic protein PACT is expressed at high levels in colonic epithelial cells in mice. Am. J. Gastrointest. Liver Physiol., 283. G801-G808.
Patel, C. V., Handy, I., Goldsmith, T., and Patel, R. C. 2000. PACT, a stress-modulated cellular activator of interferon-induced double-stranded RNA-activated protein kinase, PKR. J. Biol. Chem., 275. 37993-37998.
Patel, R. C., Vestal, D. J., Xu, Z., Bandyopadhyay, S., Guo, W., Erme, S. M., Wiliams, B. R. G. and Sen, G. C. 1999. DRBP76, a double-stranded RNA-binding nuclear protein, is phosphorylated by the interferon-induced protein kinase, PKR. J. Biol. Chem., 274. 20432-20437.
Patel, R. C., and Sen, G. C. 1998. Requirement of PKR dimerization mediated by specific hydrophobic residues for its activation by double-stranded RNA and its antigrowth effects in yeast. . Mol Cell. Biol., 18. 7009-7019.
Leaman, D. W., Salvekar, A., Patel, R. C., Sen, G. C. and Stark, G. R. 1998. A mutant cell line defective in response to double-stranded RNA and in regulating basal expression of interferon-stimulated genes. Proc. Natl. Acad. Sci. USA., 95. 9442-9447.
Patel, R. C., and Sen, G. C. 1998. PACT, a protein activator of the interferon-induced protein kinase, PKR. EMBO J., 17. 4379-4390.