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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center

 
Sandra  Zinkel

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

Contact Information:

Vanderbilt University Medical Center
2220 Pierce Ave , PRB 548
Nashville , TN 37232-6307
615-936-1801
Fax: 615-936-3853

Education
  • M.D. - University of Chicago
  • Ph.D. - Molecular Biophysics and Biochemistry, Yale University
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.

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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/26077396.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/22833394.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/23069655.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/23069655.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/23470523.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/23470523.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/22522598.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/22634010.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21859891.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21113148.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/20813900.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/20617182.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18662573.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/17632047.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16763616.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16122425.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15635450.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12533511.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11867899.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11742085.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10476969.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11232306.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8990189.
  • Zinkel S, Fuchs E. Skin cancer and transgenic mice. Semin. Cancer Biol. 1994 Feb; 5(1): 77-90. PMID: 8186391, ISSN: 1044-579X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8186391.
  • Zinkel SS, Pal SK, SzeberĂ©nyi 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1533271.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1833632.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1645410.
  • 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.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2158360.
  • 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 from: http://www.ncbi.nlm.nih.gov/pubmed/3600796.