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Dhan V. Kalvakolanu
 

Dhan V. Kalvakolanu Ph.D.

Academic Title: Professor
Primary Appointment: Microbiology and Immunology
dkalvako@umaryland.edu
Location: Howard Hall, 350
Phone: (410) 328-1396 (office)
Phone: (410) 328-1398 (lab)
Fax: (410) 706-6609
 

Personal History:

1979: BS (Biology & Chemistry), Osmania University, Hyderabad, India
1981: MS (Microbiology), Osmania University, Hyderabad, India
1988: Ph.D (Microbiology), Indian Institute of Science, Bangalore, India

Research Interests:

Dr. Kalvakolanu has extensive experience in the areas of molecular biology, Cancer Biology, Virology, cytokine induced innate immunity, Signal transduction, autophagy, apoptosis, and transcriptional regulation of gene expression. His seminal contributions include the discovery of GRIMs, a novel group of tumor suppressor genes; novel cytokine inducible gene regulatory elements, their cognate transcription factors and signal transduction pathways that control them. He is also one of the first few investigators who described mechanisms of how viral oncogenes resist Interferon actions.

Our work centers on the regulation of novel cell death-activating genes and how aberrations in these gene products influence tumor development and metastasis. Regulation of gene transcription and signal transduction by cytokines and chemokines, e.g. JAK-STAT, MAPK C/EBP, AP1 and ATF signaling pathways. The roles of endoplasmic reticulum in suppressing tumor cell growth, promoting Apoptosis and autophagy.

  1. Our lab is engaged in defining how cytokines exert direct tumor suppressive actions on tumor cells. In particular, we were interested in defining combinations of other drugs that would exert synergistic antitumor actions when combined with Interferons. Based on the proven clinical efficacy of interferon and retinoid combination in the treatment of advanced SCCs, we had set up genome-wide knockdown screens to identify GRIMs, a novel group of novel tumor suppressors. We have documented first functionally-inactivating somatic mutations and loss of expression of one of these, GRIM-19, in several different human cancers. Indeed, several cancer genome sequence databases now report several missense mutations, deletions and amplifications of GRIM-19 gene in various human tumors. Based on these we have generated a conditional knockout mouse and demonstrated that even mono-allelic loss of GRIM-19 is sufficient increase the propensity of animals to develop tumors. Until now tumor suppressors have been thought to control cell growth via a regulation of intracellular processes like division, apoptosis and adhesion. Emerging reports indicate these molecules may also regulate extracellular environment. Immune escape is a major contributor to tumor metastases. We have shown the upregulation of a chemokine wave in GRIM-19 deficient tumors. Currently, we studying how the loss/mutation of GRIM-19 favors the development of immunosuppressive microenvironment. We are also testing if blockade of these upstream regulators blocks the chemokine wave and blunts tumor progression. In this manner, this is a bed to bench and bench to bed study with strong basic and translational impact- for our studies were based on initial clinical observations, defined the candidate genes in the lab, validated their aberration in clinical samples and came back to bench for further understanding of molecular bases for tumor development. We are currently evaluating the impact of GRIM-19 on the development and progression of Head and Neck Cancers. The information gained from these studies will be useful in developing better targeted therapies for HNSCCs and other cancers.
  2. My other contribution to science is the definition of novel signal transduction pathways employed by cytokines. In particular, we have identified non JAK-STAT pathways that promote antitumor actions of interferons. Earlier we have defined a critical role for MAPK signaling pathways and transcription factor C/EBP in driving anti-tumor actions. The expression of a metastasis suppressing calcium/calmodulin dependent protein serine-threonine kinase the death associated protein kinase 1 (DAPK1) is inactivated in a number of human cancers. C/EBP- collaborates with another transcription factor ATF6, present in the endoplasmic reticulum in promoting the expression of DAPK1. We have described a role for IFN-induced proteolysis and phosphorylation dependent proteolytic activation of ATF6 in the Golgi. A novel role for apoptosis-stimulating kinase-1 (ASK1) in inducing ATF6 phosphorylation in the ER has been identified in these studies. We e have identified a novel non-canonical NF-kB/HDAC dependent axis in suppressing DAPK1 expression in acute myeloid leukemia. The current studies are focused on the role of this signal transduction pathway to lung tumor development using knockout mouse models.

Lab Techniques and Equipment:

We employ molecular and cell biological methods to understand cancer cell proliferation. We have extensive experience with protein interactions, tyrosine protein kinases of the JAK and Src families, JAK-STAT signaling, mitochondrial metabolic measurements, ChIP assays, RNAi, mass spectrometry, and RNA-seq, generation of monoclonal antibodies, knockout mice, Patient-derived tumor xenografts, metastasis, cell cylce analysis, cell growth and apoptosis.

Equipment in our lab include: Stratagene MX5003P Real time PCR machine- capable of running 5 different primer sets in the same reaction, Nanodrop spectrophotometer, Tecan F-200 Multiskan flouro-lumino-spectrophotometer, one Wallac luminometer with double port injectors, Biorad Fluorescence spectrophotometer, 3 PCR machines, BTX Electroporator, Amaxa Nucleoporator, Olympus Fluorescence microscope, and fluorescence and visual Spectrophotometers.


Publications:

  1. Zhang, J., Yang, J., Roy, S. K., Tininini, S., Hu, J., Bromberg, J. F., Poli, V., Stark, G. R. & Kalvakolanu, D. V. (2003)  The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3. Proc Natl Acad Sci U S A 100: 9342-9347. PMCID: PMC170920.
  2. Kalakonda, S., Nallar, S. C., Lindner, D. J., Hu, J., Reddy, S. P. & Kalvakolanu, D. V. (2007)  Tumor-suppressive activity of the cell death activator GRIM-19 on a constitutively active signal transducer and activator of transcription 3. Cancer Res 67: 6212-6220. PMCID in process.
  3. Sun, P., Nallar, S. C., Kalakonda, S., Lindner, D. J., Martin, S. S. & Kalvakolanu, D. V. (2009) GRIM-19 inhibits v-Src-induced cell motility by interfering with cytoskeletal restructuring. Oncogene 28: 1339-1347. PMCID: PMC2662763
  4. Sun, P., Nallar, S. C., Raha, A., Kalakonda, S., Velalar, C. N., Reddy, S. P. & Kalvakolanu, D. V. (2010)  GRIM-19 and p16(INK4a) synergistically regulate cell cycle progression and E2F1-responsive gene expression. J Biol Chem 285: 27545-27552. PMCID: PMC 2934621
  5. Nallar, S. C., Kalakonda, S., Lindner, D. J., Lorenz, R. R., Lamarre, E., Weihua, X. & Kalvakolanu, D. V. (2013)  Tumor-derived mutations in the Gene-associated with Retinoid-Interferon induced Mortality (GRIM-19) disrupt its anti-Signal transducer and activator of transcription 3 (STAT3) activity and promote oncogenesis. J Biol Chem 288: 7930-7941. PMCID: PMC3597830
  6. Kalakonda, S., Nallar, S. C., Lindner, D. J., Sun, P., Lorenz, R. R., Lamarre, E., Reddy, S. P. & Kalvakolanu, D. V. (2014)  GRIM-19 mutations fail to inhibit v-Src-induced oncogenesis. Oncogene: 33, 3195-3204. PMCID 3916943.
  7. Kalakonda, S., Nallar, S. C., Jaber, S., Keay, S. K., Rorke, E., Munivenkatappa, R., Lindner, D. J., Fiskum, G. M. & Kalvakolanu, D. V. (2013) Monoallelic loss of tumor suppressor GRIM-19 promotes tumorigenesis in mice. Proc Natl Acad Sci USA 110, E4213-4222. PMCID: PMC3831468
  8. Guha, P., Kaptan, E., Bandyopadhyaya, G., Kaczanowska, S., Davila, E., Thompson, K., Martin, S. S., Kalvakolanu, D. V., Vasta, G. R. & Ahmed, H. (2013) Cod glycopeptide with picomolar affinity to galectin-3 suppresses T-cell apoptosis and prostate cancer metastasis. Proc Natl Acad Sci USA 110, 5052-5057. PMCID: PMC3612646
  9. Gade, P., Manjegowda, S. B., Nallar, S. C., Maachani, U. B., Cross, A. S. & Kalvakolanu, D. V. (2014) Regulation of the death-associated protein kinase 1 expression and autophagy via ATF6 requires apoptosis signal-regulating kinase 1. Mol Cell Biol 34, 4033-4048. PMCID: (in process)
  10. Vaz, M., Machireddy, N., Irving, A., Potteti, H. R., Chevalier, K., Kalvakolanu, D. & Reddy, S. P. (2012) Oxidant-induced cell death and Nrf2-dependent antioxidative response are controlled by Fra-1/AP-1. Mol Cell Biol 32, 1694-1709. PMCID: PMC3347243
  11. Gade P, Ramachandran G, Maachani UB, Rizzo MA, Okada T, Prywes R, Cross AS, Mori K, Kalvakolanu DV (2012). An IFN-γ-stimulated ATF6-C/EBP-β-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy. Proc Natl Acad Sci USA 109:10316-10321. PMCID: PMC3387052.
  12. Shanmugam, R, Gade, P, Wilson-Weekes, AM, Sayar, H, Suvannasankha, A, Goswami, CP, Li, L, Gupta, SK, Cardoso, AA, Al Baghdadi, T, Sargent, KJ, Cripe, L, Kalvakolanu, DV, and Boswell, HS (2012). A non-canonical Flt3ITD/ NF-kappaB signaling pathway represses DAPK1 in acute myeloid leukemia (AML). Clin Cancer Res 18:360-369 PMCID: PMC3918433
  13. Bolesta, E, Pfannenstiel, LW, Demelash, A, Lesniewski, ML, Tobin, M, Schlanger, S, Nallar, SC, Papadimitriou, JC, Kalvakolanu, DV, and Gastman, BR (2012). Inhibition of Mcl-1 Promotes Senescence in Cancer Cells: Implications for Preventing Tumor Growth and Chemotherapy Resistance. Mol Cell Biol. 32:1879-1892; PMCID: PMC3347419
  14. Gade, P., Singh, A. K., Roy, S. K., Reddy, S. P. & Kalvakolanu, D. V. (2009) Down-regulation of the transcriptional mediator subunit Med1 contributes to the loss of expression of metastasis-associated dapk1 in human cancers and cancer cells. Int J Cancer 125, 1566-1574. PMCID: PMC 4010141
  15. Sikder, H., Zhao, Y., Balato, A., Chapoval, A., Fishelevich, R., Gade, P., Singh, I. S., Kalvakolanu, D. V., Johnson, P. F. & Gaspari, A. A. (2009) A central role for transcription factor C/EBP-beta in regulating CD1d gene expression in human keratinocytes. J Immunol 183, 1657-1666. PMCID: PMC 3891659
  16. Shen, F, Li, N, Gade, P, Kalvakolanu, DV, Weibley, T, Doble, B, Woodgett, JR, Wood, TD, and Gaffen, SL (2009). IL-17 Receptor Signaling Inhibits C/EBP{beta} by Sequential Phosphorylation of the Regulatory 2 Domain. Sci Signal 2: ra8 PMCID: PMC 2754870.
  17. Gade, P., Roy, S. K., Li, H., Nallar, S. C. & Kalvakolanu, D. V. (2008) Critical role for transcription factor C/EBP-beta in regulating the expression of death-associated protein kinase 1. Mol Cell Biol 28, 2528-2548.
  18. Roy, S. K., Hu, J., Meng, Q., Xia, Y., Shapiro, P. S., Reddy, S. P., Platanias, L. C., Lindner, D. J., Johnson, P. F., Pritchard, C., Pages, G., Pouyssegur, J. & Kalvakolanu, D. V. (2002) MEKK1 plays a critical role in activating the transcription factor C/EBP-beta-dependent gene expression in response to IFN-gamma. Proc Natl Acad Sci USA 99, 7945-7950.

Complete list of my publicaitons could be found at: http://www.ncbi.nlm.nih.gov/pubmed/?term=Kalvakolanu

Please note that is list does not include several book chapters and other invited contributions.