Sandra Zinkel, M.D., Ph.D.
Assistant Professor of Medicine (Hematology/Oncology)
Assistant Professor of Cell & Developmental Biology
Assistant Professor of Cancer Biology
Medical Oncologist, Hematologist
Vanderbilt University Medical Center
2220 Pierce Ave , PRB 548
Nashville , TN 37232-6307
- M.D. - University of Chicago
- Ph.D. - Molecular Biophysics and Biochemistry, Yale University
BCL-2 family, BID, programmed cell death, hematopoiesis, Stem cells, DNA damage response, leukemia, Apoptosis, Biochemistry, Cancer, Cell cycle, DNA repair, Knockout, Mass spectroscopy, Mouse, Phosphorylation, Proteomics, Signal transduction
My lab is interested in understanding the mechanisms by which normal and malignant cells regulate programmed cell death. Multicellular organisms have devised a tightly regulated, genetically programmed mechanism of cell suicide to maintain homeostasis and to prevent propagation of genetically damaged cells. The discovery of the BCL-2 family of genes uncovered the underlying genetic mechanism of this regulation, as well as a class of oncogenes that governs cell death rather than cell proliferation.
There are two major pathways that regulation programmed cell death: apoptosis and programmed necrosis. Simply, apoptotic cells implode in a relatively immune silent manner. Necrotic cells explode, releasing cellular contents and inciting an immune response- beneficial in settings of infection, but detrimental in settings of chronic damage, where the inflammation eliicited by necrotic cell death amplifies cellular damage. Current studies focus on how programmed cell death regulates homeostasis in the hematopoietic (blood) system. We have found that unrestrained programmed necrosis leads to bone marrow failure in mice that closely resembles the human disease Myelodysplastic syndrome (MDS).
The projects in my lab use hematopoietic cell culture systems, mouse models, immunofluorescence, electron microscopy, as well as flow cytometry and cell death assays to understand the signals and protein interactions that direct hematopoietic cells to die by apoptosis or necrosis. In addition, we use our mouse models to determine the effects of inhibiting necrosis on bone marrow failure and transformation to leukemia. An additional focus is to dissect the mechanism of Bcl-2 family members in mouse models of leukemia. Our studies provide new insights into the interplay between apoptosis and necrosis, and their role in hematopoiesis, bone marrow failure, and leukemogenesis.
- Yin, H, Vergeade, A, Shi, Q, Zackert, WE, Gruenberg, KC, Bokiej, M, Amin, T, Ying, W, Masterson, TS, Zinkel, SS, Oates, JA, Boutaud, O, Roberts, LJ Acetaminophen inhibits cytochrome c redox cycling induced lipid peroxidation. Biochem Biophys Res Commun, 423(2), 224-8, 2012.
- Liu, Y, Aiello, A, Zinkel, SS Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress. Cell Death Differ, 2012.
- Liu, Y, Vaithiyalingam, S, Shi, Q, Chazin, WJ, Zinkel, SS BID binds to Replication protein A and stimulates ATR function following replicative stress. Mol Cell Biol, 2011.
- Liu, Y, Bertram, CC, Shi, Q, Zinkel, SS Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress. Cell Death Differ, 18(5), 841-52, 2011.
- Biswas, S, Shi, Q, Matise, L, Cleveland, S, Dave, U, Zinkel, S A role for proapoptotic Bax and Bak in T-cell differentiation and transformation. Blood, 116(24), 5237-46, 2010.
- Danthi, P, Pruijssers, AJ, Berger, AK, Holm, GH, Zinkel, SS, Dermody, TS Bid regulates the pathogenesis of neurotropic reovirus. PLoS Pathog, 6e1000980, 2010.
- Zinkel, SS Investigation of the proapoptotic BCL-2 family member bid on the crossroad of the DNA damage response and apoptosis. Methods Enzymol, 442231-50, 2008.
- Zinkel, SS, Hurov, KE, Gross, A Bid plays a role in the DNA damage response. Cell, 130(1), 9-10; author reply 10-1, 2007.
- Zinkel, S, Gross, A, Yang, E BCL2 family in DNA damage and cell cycle control. Cell Death Differ, 2006.
- Zinkel, SS, Hurov, KE, Ong, C, Abtahi, FM, Gross, A, Korsmeyer, SJ A role for proapoptotic BID in the DNA-damage response. Cell, 122(4), 579-91, 2005.
- Wang, J, Iwasaki, H, Krivtsov, A, Febbo, PG, Thorner, AR, Ernst, P, Anastasiadou, E, Kutok, JL, Kogan, SC, Zinkel, SS, Fisher, JK, Hess, JL, Golub, TR, Armstrong, SA, Akashi, K, Korsmeyer, SJ Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease. EMBO J, 24(2), 368-81, 2005.
- Zinkel, SS, Ong, CC, Ferguson, DO, Iwasaki, H, Akashi, K, Bronson, RT, Kutok, JL, Alt, FW, Korsmeyer, SJ Proapoptotic BID is required for myeloid homeostasis and tumor suppression. Genes Dev, 17(2), 229-39, 2003.
- Plesnila, N, Zinkel, S, Amin-Hanjani, S, Qiu, J, Korsmeyer, SJ, Moskowitz, MA Function of BID -- a molecule of the bcl-2 family -- in ischemic cell death in the brain. Eur Surg Res, 34(1-2), 37-41, 2002.
- Plesnila, N, Zinkel, S, Le, DA, Amin-Hanjani, S, Wu, Y, Qiu, J, Chiarugi, A, Thomas, SS, Kohane, DS, Korsmeyer, SJ, Moskowitz, MA BID mediates neuronal cell death after oxygen/ glucose deprivation and focal cerebral ischemia. Proc Natl Acad Sci U S A, 98(26), 15318-23, 2001.
- Yin, XM, Wang, K, Gross, A, Zhao, Y, Zinkel, S, Klocke, B, Roth, KA, Korsmeyer, SJ Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature, 400(6747), 886-91, 1999.
- Korsmeyer, SJ, Gross, A, Harada, H, Zha, J, Wang, K, Yin, XM, Wei, M, Zinkel, S Death and survival signals determine active/inactive conformations of pro-apoptotic BAX, BAD, and BID molecules. Cold Spring Harb Symp Quant Biol, 64343-50, 1999.
- Wang, X, Zinkel, S, Polonsky, K, Fuchs, E Transgenic studies with a keratin promoter-driven growth hormone transgene: prospects for gene therapy. Proc Natl Acad Sci U S A, 94(1), 219-26, 1997.
- Zinkel, S, Fuchs, E Skin cancer and transgenic mice. Semin Cancer Biol, 5(1), 77-90, 1994.
- Zinkel, SS, Pal, SK, SzeberÃ©nyi, J, Cooper, GM Identification of a negative regulatory element that inhibits c-mos transcription in somatic cells. Mol Cell Biol, 12(5), 2029-36, 1992.
- Zinkel, SS, Crothers, DM Catabolite activator protein-induced DNA bending in transcription initiation. J Mol Biol, 219(2), 201-15, 1991.
- Pal, SK, Zinkel, SS, Kiessling, AA, Cooper, GM c-mos expression in mouse oocytes is controlled by initiator-related sequences immediately downstream of the transcription initiation site. Mol Cell Biol, 11(10), 5190-6, 1991.
- Zinkel, SS, Crothers, DM Comparative gel electrophoresis measurement of the DNA bend angle induced by the catabolite activator protein. Biopolymers, 29(1), 29-38, 1990.
- Zinkel, SS, Crothers, DM DNA bend direction by phase sensitive detection. Nature, 328(6126), 178-81, 1987.