Sandra Zinkel, M.D., Ph.D.
Assistant Professor of Medicine (Hematology/Oncology)
Assistant Professor of Cancer Biology and Cell & Developmental Biology
Medical Oncologist, Hematologist
Vanderbilt University Medical Center
2220 Pierce Ave , PRB 548
Nashville , TN 37232-6307
BCL-2 family, BID, DNA damage response, leukemia, Apoptosis, Biochemistry, Cancer, Cell cycle, DNA repair, Knockout, Mass spectroscopy, Mouse, Phosphorylation, Proteomics, Signal transduction, Stem cells
My lab is interested in understanding the mechanisms by which normal and malignant cells regulate programmed cell death or apoptosis following DNA damage. 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.
Current studies focus on the pro-death BCL-2 family member BID. The deletion of BID in mice prolongs the lives of myeloid cells culminating in the development of a fatal disorder resembling the human disease chronic myelomonocytic leukemia (CMML). Our recent work has shown an additional role for BID in preserving genomic integrity that is distinct from its pro-apoptotic role. Following DNA damage, BID is phosphorylated by the DNA damage kinase ATM and plays a role in cell cycle checkpoint control. Cells initiate a complex series of responses subsequent to DNA damage including activation of cell cycle checkpoints, promoting DNA repair, or activating apoptosis. BID, with its dual function in apoptosis and the DNA damage response, is well situated to serve as a mediator in determining cell fate following DNA damage.
An additional focus of the lab is on the role of the Bcl-2 family of proteins in hematopoietic differentiation and stem cell function.
The projects in my lab use hematopoietic cell culture systems, mouse models, immunofluorescence, as well as apoptosis, cell cycle checkpoint and DNA repair assays to understand the signals and protein interactions that direct BID to assume an apoptotic or cell cycle checkpoint/DNA repair role following treatment with agents inducing DNA damage. 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 cell cycle checkpoint/DNA repair responses following DNA damage, and their role in myeloid homeostasis 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.
- M.D. - University of Chicago
- Ph.D. - Molecular Biophysics and Biochemistry, Yale University