Sandra S. Zinkel, Ph.D., M.D.

Associate Professor

sandra.zinkel@vanderbilt.edu
Faculty Appointments
Associate Professor of Medicine Associate Professor of Cancer BiologyAssociate Professor of Cell and Developmental Biology
Education
M.D., Medicine, University of Chicago, Chicago, IllinoisPh.D., Molecular Biophysics and Biochemistry, Yale University, New Haven, ConnecticutB.S., Chemistry, Indiana University, Indianapolis, IndianaB.S., Music, Indiana University, Bloomington, Indiana
Office Address
548 PRB
2220 Pierce Avenue
Nashville, TN 6307
Research Description
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.
Research Keywords
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
Publications
Zhou T, Kinney MC, Scott LM, Zinkel SS, Rebel VI. Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research. Blood [print-electronic]. 2015 Aug 8/27/2015; 126(9): 1057-68. PMID: 26077396, PMCID: PMC4551359, PII: blood-2015-01-624239, DOI: 10.1182/blood-2015-01-624239, ISSN: 1528-0020.

Williams CS, Bradley AM, Chaturvedi R, Singh K, Piazuelo MB, Chen X, McDonough EM, Schwartz DA, Brown CT, Allaman MM, Coburn LA, Horst SN, Beaulieu DB, Choksi YA, Washington MK, Williams AD, Fisher MA, Zinkel SS, Peek RM, Wilson KT, Hiebert SW. MTG16 contributes to colonic epithelial integrity in experimental colitis. Gut [print-electronic]. 2013 Oct; 62(10): 1446-55. PMID: 22833394, PMCID: PMC3663894, PII: gutjnl-2011-301439, DOI: 10.1136/gutjnl-2011-301439, ISSN: 1468-3288.

Zinkel SS, Yin XM, Gross A. Rejuvenating Bi(d)ology. Oncogene [print-electronic]. 2013 Jul 7/4/2013; 32(27): 3213-9. PMID: 23069655, PMCID: PMC4037911, PII: onc2012454, DOI: 10.1038/onc.2012.454, ISSN: 1476-5594.

Zinkel SS, Yin XM, Gross A. Rejuvenating Bi(d)ology. Oncogene [print-electronic]. 2013 Jul 7/4/2013; 32(27): 3213-9. PMID: 23069655, PMCID: PMC4037911, PII: onc2012454, DOI: 10.1038/onc.2012.454, ISSN: 1476-5594.

Biswas S, Shi Q, Wernick A, Aiello A, Zinkel SS. The loss of the BH3-only Bcl-2 family member Bid delays T-cell leukemogenesis in Atm-/- mice. Cell Death Differ [print-electronic]. 2013 Jul; 20(7): 869-77. PMID: 23470523, PMCID: PMC3679453, PII: cdd201316, DOI: 10.1038/cdd.2013.16, ISSN: 1476-5403.

Biswas S, Shi Q, Wernick A, Aiello A, Zinkel SS. The loss of the BH3-only Bcl-2 family member Bid delays T-cell leukemogenesis in Atm-/- mice. Cell Death Differ [print-electronic]. 2013 Jul; 20(7): 869-77. PMID: 23470523, PMCID: PMC3679453, PII: cdd201316, DOI: 10.1038/cdd.2013.16, ISSN: 1476-5403.

Liu Y, Aiello A, Zinkel SS. Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress. Cell Death Differ [print-electronic]. 2012 Oct; 19(10): 1602-12. PMID: 22522598, PMCID: PMC3438491, PII: cdd201238, DOI: 10.1038/cdd.2012.38, ISSN: 1476-5403.

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 [print-electronic]. 2012 Jun 6/29/2012; 423(2): 224-8. PMID: 22634010, PMCID: PMC3389218, PII: S0006-291X(12)00935-7, DOI: 10.1016/j.bbrc.2012.05.058, ISSN: 1090-2104.

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 [print-electronic]. 2011 Nov; 31(21): 4298-309. PMID: 21859891, PMCID: PMC3209332, PII: MCB.05737-11, DOI: 10.1128/MCB.05737-11, ISSN: 1098-5549.

Liu Y, Bertram CC, Shi Q, Zinkel SS. Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress. Cell Death Differ [print-electronic]. 2011 May; 18(5): 841-52. PMID: 21113148, PMCID: PMC3074003, PII: cdd2010151, DOI: 10.1038/cdd.2010.151, ISSN: 1476-5403.

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 [print-electronic]. 2010 Dec 12/9/2010; 116(24): 5237-46. PMID: 20813900, PMCID: PMC3012541, PII: blood-2010-04-279687, DOI: 10.1182/blood-2010-04-279687, ISSN: 1528-0020.

Danthi P, Pruijssers AJ, Berger AK, Holm GH, Zinkel SS, Dermody TS. Bid regulates the pathogenesis of neurotropic reovirus. PLoS Pathog. 2010; 6: e1000980. PMID: 20617182, PMCID: PMC2895667, DOI: 10.1371/journal.ppat.1000980, ISSN: 1553-7374.

Zinkel SS. Investigation of the proapoptotic BCL-2 family member bid on the crossroad of the DNA damage response and apoptosis. Meth. Enzymol. 2008; 442: 231-50. PMID: 18662573, PII: S0076-6879(08)01412-2, DOI: 10.1016/S0076-6879(08)01412-2, ISSN: 1557-7988.

Zinkel SS, Hurov KE, Gross A. Bid plays a role in the DNA damage response [letter]. Cell. 2007 Jul 7/13/2007; 130(1): 9-10; author reply 10. PMID: 17632047, PII: S0092-8674(07)00840-9, DOI: 10.1016/j.cell.2007.06.035, ISSN: 0092-8674.

Zinkel S, Gross A, Yang E. BCL2 family in DNA damage and cell cycle control. Cell Death Differ [print-electronic]. 2006 Aug; 13(8): 1351-9. PMID: 16763616, PII: 4401987, DOI: 10.1038/sj.cdd.4401987, ISSN: 1350-9047.

Zinkel SS, Hurov KE, Ong C, Abtahi FM, Gross A, Korsmeyer SJ. A role for proapoptotic BID in the DNA-damage response. Cell. 2005 Aug 8/26/2005; 122(4): 579-91. PMID: 16122425, PII: S0092-8674(05)00641-0, DOI: 10.1016/j.cell.2005.06.022, ISSN: 0092-8674.

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 [print-electronic]. 2005 Jan 1/26/2005; 24(2): 368-81. PMID: 15635450, PMCID: PMC545811, PII: 7600521, DOI: 10.1038/sj.emboj.7600521, ISSN: 0261-4189.

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. 2003 Jan 1/15/2003; 17(2): 229-39. PMID: 12533511, PMCID: PMC195974, DOI: 10.1101/gad.1045603, ISSN: 0890-9369.

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. 2002 Jan; 34(1-2): 37-41. PMID: 11867899, PII: 48885, DOI: 48885, ISSN: 0014-312X.

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 [print-electronic]. 2001 Dec 12/18/2001; 98(26): 15318-23. PMID: 11742085, PMCID: PMC65027, PII: 261323298, DOI: 10.1073/pnas.261323298, ISSN: 0027-8424.

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. 1999 Aug 8/26/1999; 400(6747): 886-91. PMID: 10476969, DOI: 10.1038/23730, ISSN: 0028-0836.

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. 1999; 64: 343-50. PMID: 11232306, ISSN: 0091-7451.

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. 1997 Jan 1/7/1997; 94(1): 219-26. PMID: 8990189, PMCID: PMC19291, ISSN: 0027-8424.

Zinkel S, Fuchs E. Skin cancer and transgenic mice. Semin. Cancer Biol. 1994 Feb; 5(1): 77-90. PMID: 8186391, ISSN: 1044-579X.

Zinkel SS, Pal SK, Szeberényi J, Cooper GM. Identification of a negative regulatory element that inhibits c-mos transcription in somatic cells. Mol. Cell. Biol. 1992 May; 12(5): 2029-36. PMID: 1533271, PMCID: PMC364373, ISSN: 0270-7306.

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. 1991 Oct; 11(10): 5190-6. PMID: 1833632, PMCID: PMC361551, ISSN: 0270-7306.

Zinkel SS, Crothers DM. Catabolite activator protein-induced DNA bending in transcription initiation. J. Mol. Biol. 1991 May 5/20/1991; 219(2): 201-15. PMID: 1645410, PII: 0022-2836(91)90562-K, ISSN: 0022-2836.

Zinkel SS, Crothers DM. Comparative gel electrophoresis measurement of the DNA bend angle induced by the catabolite activator protein. Biopolymers. 1990 Jan; 29(1): 29-38. PMID: 2158360, DOI: 10.1002/bip.360290106, ISSN: 0006-3525.

Zinkel SS, Crothers DM. DNA bend direction by phase sensitive detection. Nature. 1987 Jul 7/9/1987; 328(6126): 178-81. PMID: 3600796, DOI: 10.1038/328178a0, ISSN: 0028-0836.

Available Postdoctoral Position Details
Posted: 2/16/2016
The Zinkel Lab in the Department of Medicine at Vanderbilt University School of Medicine is seeking a highly-motivated individual to join our team to investigate the mechanism by which aberrations in Programmed cell death (apoptosis and programmed necrosis or necroptosis) drives bone marrow failure or leukemogenesis through modulating blood cell development, hematopoietic stem and progenitor cell function, and the bone marrow microenvironment. Our work focuses on elucidating the molecular mechanisms of programmed cell death determination to identify and test targets for therapeutic intervention. The successful candidate will have a PhD and/or MD with experience in molecular and cellular biology and a solid publication record. Vanderbilt offers a highly collaborative research environment focused on interdisciplinary research. Please send a curriculum vita, the names of three references, and a letter describing your research interests to: Dr. Sandra Zinkel (Sandra.zinkel@vanderbilt.edu).