Laxminarayana Devireddy, D.V.M., Ph.D.Assistant Professor
2103 Cornell Rd.
Cleveland, OH 44106-7288
phone: (216) 368-1513
fax: (216) 368-0494
Dr. Devireddy obtained his DVM degree from A.P. Agricultural University in Hyderabad, India. He later attended Indian Institute of Science (IISC) in Bangalore to pursue a Mater's degree in Virology. He then enrolled in an interdisciplinary graduate program at University of Nebraska Medical Center studying the latency of herpes viruses under the guidance of Dr. Clinton Jones. After graduation he joined Prof. Michael Green's laboratory at University of Massachusetts to study the transcriptional regulation of apoptosis. His postdoctoral studies were funded by fellowships from Leukemia and Lymphoma Society and Howard Temin Award from NCI. In the fall of 2006 he accepted a faculty position in the Department of Pathology/Case Comprehensive Cancer Center at Case Western Reserve University. At Case he studies regulation of apoptosis by newly discovered Lipocalin. He is also interested in analyzing the role of Lipocalin in normal physiology and myeloproliferative disease.
Apoptosis is a critical aspect of both the genesis and treatment of cancer. Apoptotic cell death is an essential part of lymphocyte maintenance, with the loss of survival signal, such as a cytokine, as a principal trigger of cell death. There is substantial evidence that growth factor withdrawal- induced apoptosis may be transcriptionally dependent and the genes that are differentially regulated upon factor withdrawal induce apoptosis. Using DNA microarrays to analyze IL-3-dependent lymphocytes, we found that the gene undergoing maximal transcriptional induction following cytokine withdrawal is 24p3, which encodes a secreted Lipocalin.
Lipocalins are small-secreted proteins grouped into one superfamily based on sequence and structural similarities. All are known to form a squat β-barrel like cavity that serves as a docking site for small hydrophobic ligands. They are known to influence a plethora of cellular functions by delivering their cargo in a receptor-dependent process. Lipocalin 24p3, also known as NGAL, Lcn2, Siderocalin, and Uterocalin is implicated in disparate biological processes such as apoptosis, innate immunity, and organogenesis. Most recent work demonstrated that Lipocalin 24p3 is an iron binding protein. Interestingly, 24p3 doesn't have an intrinsic ability to bind iron but rather a small molecule called siderophore mediates the iron binding.
My tenure in Prof. Michael Green's laboratory studied the role of Lipocalin 24p3 in cytokine- deprivation induced apoptosis. 24p3 is stimulated upon cytokine withdrawal, and the secreted Lipocalin induces apoptosis in an autocrine/paracrine fashion. This process is dependent upon the expression a receptor specific for 24p3. We have isolated by expression cloning a cDNA encoding a cell surface receptor specific for 24p3 (24p3R). Ectopic expression of 24p3R confers on cells the ability to undergo 24p3-dependent iron uptake or apoptosis. The differential response is controlled by the iron status of 24p3: iron-loaded 24p3 (holo-24p3) increases intracellular iron levels without inducing apoptosis; iron-lacking 24p3 (apo-24p3) decreases intracellular iron levels resulting in apoptosis. Intracellular iron delivery suppresses apoptosis due to addition of 24p3 or IL-3 deprivation. However, it is not entirely clear the basis by which decreased intracellular iron induces apoptosis. I will continue to characterize the apoptotic pathway induced by 24p3 and by iron chelators. We have also found that BCR-ABL oncoprotein differentially regulates the expression of 24p3 and 24p3R. The down-regulation of 24p3R renders BCR-ABL+ cells refractory to the secreted 24p3. These results reveal a new and unanticipated aspect of the mechanism by which BCR-ABL promotes cell survival.
My long-term goal is to understand the role of 24p3/24p3R pathway in normal physiology and myeloproliferative disease. My future research goals are:
- Characterization of 24p3/24p3R apoptotic pathway: Lipocalin 24p3 induces apoptosis through a novel pathway culminating in decreased intracellular iron levels. A variety of evidence suggests that apoptosis due to iron-deprivation involves differential gene expression. Expression profiling and RNAi will be used to identify the transcriptionally altered genes in 24p3- and iron-chelator-mediated apoptosis.
- Role of 243p in lymphoid malignancies: We have found that the transcription of 24p3 and 24p3R is profoundly misregulated in cells transformed by BCR-ABL. I will study the generality of this result; determine whether expression of 24p3 and 24p3R is also misregulated in cells transformed by other fusion oncogenic tyrosine kinases. I will study the basis by which 24p3 and 24p3R transcription is misregulated. Preliminary results also suggest that the 24p3 apoptotic pathway contributes to lymphoid malignancies. I will study the role of 24p3 in these malignancies utilizing well- established murine models.
Devireddy, L.R., C. Gazin, X. Zhu and M. R. Green. (2005). A cell surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell. 123: 1293-1305.
Devireddy, L.R and Y. Zhang and C.J. Jones (2003). Cloning and initial characterization of an alternatively spliced transcript encoded by the bovine herpes virus 1 latency-related gene. Journal of Neurovirology. 9: 612-622.
Devireddy, L.R and M.R. Green. (2003). A transcriptional program of apoptosis induction following IL- 2 deprivation: Identification of RC3, a calcium/calmodulin binding protein, as a novel pro-apoptotic factor. Molecular & Cellular Biology. 23: 4532-4541.
Persengiev, S.P., L.R. Devireddy and M.R. Green (2002). Inhibition of apoptosis by ATFx: a novel role for a member of the ATF/CREB family of mammalian bZIP transcription factors. Genes & Development. 16: 1806- 1814.
Devireddy, L.R., J.G. Teodoro, F.A. Richard and M.R. Green. (2001). Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation. Science. 293: 829-834.
Devireddy, L.R and C.J. Jones. (2000). Olf-1, a neuron-specific transcription factor, can activate the expression of herpes simplex virus type 1 (HSV-1) infected cell protein 0 (ICP0) promoter. Journal of Biological Chemistry. 275: 77-81.
Devireddy, L.R., K.U. Kumar, M.M. Pater. and A. Pater. (2000). BAG-1, a novel Bcl-2 interacting protein activates expression of human JC virus. Journal of General Virology. 81: 351-357.
Devireddy, L.R and C.J. Jones. (1999). Activation of caspases and p53 by Bovine herpes virus-1 (BHV- 1) infection results in programmed cell death and efficient virus release. Journal of Virology. 73: 3778- 3788.
Devireddy, L.R., R. Raghavan, S. Ramachandran and M.S. Shaila (1999). The fusion protein of peste des petits ruminants virus is a hemolysin. Archives of Virology. 144: 1241-1247.
Devireddy, L.R and C.J. Jones (1998). Alternative splicing of latency related transcript of bovine herpes virus-1 yields RNAs containing unique open reading frames. Journal of Virology. 72: 7294-7301.
Devireddy, L.R., R. Raghavan, S. Ramachandran and S.M. Subbarao (1998). Protection of rabbits against lapinized rinderpest virus with purified envelope glycoproteins of pest-des-petits-ruminants and rinderpest viruses. Acta Virologica. 42: 299-306.
Devireddy, L.R., K.U. Kumar, M.M. Pater and A. Pater (1996). Evidence for a mechanism of demyelination by Human JC virus: Negative transcriptional regulation of RNA and protein levels from myelin basic protein gene by large tumor antigen in human glioblastoma cells. Journal of Medical Virology. 49: 205-211.
Kumar, KU., L.R. Devireddy, M.M. Pater and A. Pater (1996). Human JC virus cAMP response elements functional for enhanced glial cell expression in differentiating embryonal carcinoma cells. Virology. 215: 178-185.
Kumar, K.U., L.R. Devireddy, S.-C. Tang, A. Pater and M.M. Pater (1996). Human JC virus nuclear factor I binding motifs and large tumor antigen region required for transactivation of late promoter. Journal of Neurochemistry. 67: 473-481.