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Jill Bargonetti, Professor of Biological Sciences

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Office: Rm 400 Belfer Research Building

413 East 69th Street

New York, NY 10021

Mail Box 180
Phone: (212)896-0465

Lab Web Site:http://bargonetti.bioweb.hunter.cuny.edu

Education:

  • Postdoc., 1990-1994 Columbia University
  • Ph.D., 1990 New York University
  • B.A., 1985 SUNY College at Purchase

Research Interest:

 

Link to PubMed Articles: www.ncbi.nlm.nih.gov/pubmed

 

Signal transduction to- and from- wild-type p53, mutant p53, and MDM2 isoforms in cancer.  

Signal transduction pathways converging on the tumor suppressor p53 are central in the regulation of cell growth and cell death. Conventional chemotherapeutics result in p53 checkpoint activation. However, when the p53 pathway is blocked, or mutated, a more targeted chemotherapeutic approach is required to result in an outcome of cancer cell death. A focus on such targeted approaches are central to the research being carried out in the Bargonetti laboratory.   The work focuses on the molecular signal transduction pathways activated by various chemotherapeutic drugs to bring about differential activation of p53 target genes as well as to activate alternative p53-independent cell death pathways that facilitate killing resistant cancer types. Presently this work is carried out using human cancer cell line models as well as with a C. elegans nematode model system.  The Bargonetti team recently defined a novel gain-of-function mutant p53 pathway that they termed the mtp53-PARP-MCM axis. This mtp53-PARP-MCM axis can be targeted using a PARP inhibitor that traps PARP on chromatin.

The Bargonetti research team is using genetically engineered tools to decrease the expression of three oncogenes (i.e. Mdm2, MdmX, and oncogenic mutant p53) because we hypothesize that these biomarkers are involved in the formation of different subtypes of breast cancer. They discovered that reducing the amount of Mdm2 or mutant p53 protein in breast cancer cells reduces tumor growth and abnormal architecture in three-dimensional (3D) cell culture models. We identified that estrogen receptor positive (ER+) breast cancer cells possess an Mdm2-associated growth activation pathway.  Their work has been instrumental for introducing the concept of an estrogen driven signaling pathway that uses a non-canonical Mdm2 molecular mechanism. They are delineating the molecular targets of estrogen driven Mdm2 isoforms by using genetically engineered human breast cancer cell lines to selectively rid the cancer cells of either  Mdm2, MdmX, or oncogenic mutant p53 in order to  dissect the critical targets that promote tumorigenesis. Estrogen receptor positive (ER+) breast cancers often have high levels of Mdm2 and ER negative (ER-) breast cancers often have mutant p53. They are dissecting the relevant targets of Mdm2, MdmX, and oncogenic mutant p53 in different subtypes of breast cancer.

Many cancer cells have high levels of the oncogenic Mdm2 protein due to either increased expression or amplification of the mdm2 gene. The Bargonetti group investigates alternative forms of MDM2, inclusing MDM2-FL and MDM2-C, that are expressed when a single nucleotide polymorphism (SNP) at position 309 in the mdm2 gene that causes increased Mdm2 overexpression. This overexpression can inhibit wild-type p53 activity but also causes p53-independent oncogenic functions in cells expressing mutant p53.

Bargonetti was awarded the prestigious Presidential Early Career Award for Scientists and Engineers by President Bill Clinton in 1997, and has received research grants from the American Cancer Society, The Department of Defense, the National Science Foundation and the National Institutes of Health. She is currently funded by the Breast Cancer Research Foundation. She won a Young Investigator Award, given by the mayor of New York City, the New York Voice Award, given to those who have made a significant improvement to the quality of life in New York City, and the Kathy Keeton Mountain Top Award from the New York branch of the NAACP. Bargonetti currently receives invitations to deliver lectures on both on research activities and on Choreographing Genomics into Understanding. See the PBS and TEDx/CUNY specials to get a closer view:
 





Selected Publications

  • Kundu, N., Brekman, A., Kim, J. Y., Xiao, G., Gao, C., and Bargonetti, J. Estrogen-activated MDM2 disrupts mammary tissue architecture through a p53-independent pathway, Oncotarget May 24, 2017. PMID: 28615518
  • Qiu WG, Polotskaia A, Xiao G, Di L, Zhao Y, Hu W, Philip J, Hendrickson RC, Bargonetti J. Identification, validation, and targeting of the mutant p53-PARP-MCM chromatin axis in triple negative breast cancer. NPJ Breast Cancer 2017 Feb; 3. pii: 1. doi: 10.1038/s41523-016-0001-7 PMID: 28232952
  • Shtraizent N, Matsui H, Polotskaia A, Bargonetti J. Hot Spot Mutation in TP53 (R248Q) Causes Oncogenic Gain-of-Function Phenotypes in a Breast Cancer Cell Line Derived from an African American patient. Int J Environ Res Public Health. 2015 Dec 22;13(1) . pii: E22. doi: 10.3390/ijerph13010022. PMID: 2670366
  • Rosso M, Polotskaia A, Bargonetti J. Homozygous mdm2 SNP309 cancer cells with compromised transcriptional elongation at p53 target genes are sensitive to induction of p53-independent cell death. Oncotarget. 2015 Oct 27;6(33):34573-91. doi: 10.18632/oncotarget.5312. PMID: 26416444
  • Pfister NT, Fomin V, Regunath K, Zhou JY, Zhou W, Silwal-Pandit L, Freed-Pastor WA, Laptenko O, Neo SP, Bargonetti J, Hoque M, Tian B, Gunaratne J, Engebraaten O, Manley JL, Børresen-Dale AL, Neilsen PM, Prives C. Mutant p53 cooperates with SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells. Genes Dev. 2015 Jun 15;29(12):1298-315. doi: 10.1101/gad.263202.115. Epub 2015 Jun 16. PMID: 26080815
  • Polotskaia, A., Xiao, G., Reynoso, K., Hendrickson, R., Martin, C., Qui, W. and J. Bargonetti. Proteome-wide Analysis of Mutant p53 Targets in Breast Cancer Identifies New Levels of Gain-of-Function that Influence PARP, PCNA and MCM4. (2015) Proc Natl Acad Sci U S A.;112(11):E1220-9.
  • Xiao, G., Kue, P., Bhosle and J. Bargonetti. Decarbamoyl Mitomycin C (DMC) Activates p53-independent Ataxia Telangiectasia and Rad3 Related Protein (ATR) Chromatin Eviction. (2015) Cell Cycle Epub ahead of print Jan 7. PMID: 25565400
  • Shi, M., Shtraizent, N.,  Polotskaia, A., Bargonetti, J. H. Matsui. Impedimetric Detection of Mutant p53 Biomarker-Driven Metastatic Breast Cancers under Hyposmotic Pressure. (2014) PloS One Jan 7;9(6):e99351
  • Hoffman S.,  Martin, D., Melendez A. and J. Bargonetti C. elegans p53 and Beclin 1 are involved in DNA repair. (2014) PloS One Feb 20;9(2):e88828. 
  • Shi, M., Shtraizent, N.,  Polotskaia, A., Bargonetti, J. H. Matsui. Impedimetric Detection of Mutant p53 Biomarker-Driven Metastatic Breast Cancers under Hyposmotic Pressure. (2014) PloS One Jan 7;9(6):e99351
  • Okoro D., Arva N., Gao, C., Polotskaia A., Puente, C., Rosso, M., and J. Bargonetti. Endogenous Human MDM2-C is Highly Expressed in Human Cancers and Functions as a p53-independent Growth Activator. (2013) PloS One Oct 11;8(10):e77643.
  • Catalina-Rodriguez, O., Preet, A., Kolukula, V., Furth, P., Albanese, C, Bargonetti, J. and M.L. Avantaggiati. Dietary regulation of p53 mutant levels influences tumorigenesis. (2012) Cell Cycle. 2012 Nov 14;11(23)
  • Polotskaia, A., Krett, N., Shanmugam, M., Gamss, S., Rosen, S., and Bargonetti J. 8-Aminoadenosine activates p53-independent cell death of metastatic breast cancers. (2012) Molecular Cancer Therapeutics.
  • Okoro D., Rosso M., and J. Bargonetti. Splicing up Mdm2 for Cancer Proteome Diversity. Genes & Cancer August 2012. 
  • Freed-Pastor, W. A., Mizuno, H., Zhao, X., Langerod, A., Moon, S.-H., Rodriguez-Barrueco, R., Barsotti, A., Chicas, A., Li, W., Polotskaia, A., Bissell, M. J., Osborne, T. F., Tian, B., Lowe, S. W., Silva, J. M., Borrensen-Dale, A.-L., J., L. A., Bargonetti, J., and Prives, C. (2012) Mutant p53 Disrupts Mammary Acinar Morphogenesis via the Mevalonate Pathway, Cell 148(1-2):244-58.
  • Success in Molecular Genetics: The Pink Flower" in Voices of Black American Pioneers, edited by Vernon Farmer, Greenwood Publishing Group, Westport, Connecticut (2012). 
  • Brekman, A., Singh K.E., Polotskaiai A., Kundu N. and Bargonetti J. A p53-independent role of Mdm2 in estrogen-mediated activation of breast cancer cell proliferation. (2011) Breast Cancer Res. 13 (1):R3
  • Boamah, E.K., Brekman, A., Tomasz, M.., Myeku, N., Figueiredo-Pereira, M., Hunter, S., Meyer, J. Bhosle, R.C. and Bargonetti, J. DNA adducts of decarbamoyl mitomycin C efficiently kill cells without wild-type p53 resulting from proteasome-mediated degradation of Checkpoint Protein 1.  (2010)  Chem. Res. Toxicol. 19 (23): 1151-62
  • Bargonetti, J., Champeil E. and Tomasz, M. Differential Toxicity of DNA Adducts of Mitomycin C. (2010) Invited Review Journal of Nucleic Acids. Jul 29;2010. pii: 698960
  • Paz, M.M., Ladwa, S., Champell, E., Liu, Y., Rockwell, S. Boamah, E.K., Bargonetti, J., Callahan, J., Roach, J., and Tomasz, M. Mapping DNA Adducts of Mitomycin and Decarbamoyl Mitomycin C in cell Lines Using Liquid Chromatogrphy/ Electrospray Tandem Mass Spectrometry. (2008) Chem. Res. Toxicol., 21(12): 2370-2378.
  • Arva, N., Talbott, K., Okoro, D., Brekman, A., Qiu, W., and Bargonetti, J. Disruption of the p53-Mdm2 Complex by Nutlin-3 Reveals Different Cancer Cell Phenotypes. (2008)  Ethnicity and Disease, 18(2 Suppl 2):S2-1-8.
  • Boamah EK, White DE, Talbott KE, Arva NC, Berman D, Tomasz M, Bargonetti J. Mitomycin-DNA adducts induce p53-dependent and p53-independent cell death pathways. ACS Chem Biol. 2007 Jun 15;2(6):399-407. Epub 2007 May 25.
  • White DE, Talbott KE, Arva NC, Bargonetti J. Mouse double minute 2 associates with chromatin in the presence of p53 and is released to facilitate activation of transcription. Cancer Res. 2006 Apr 1;66(7):3463-70.
  • Hui L, Zheng Y, Yan Y, Bargonetti J, Foster DA. Mutant p53 in MDA-MB-231 breast cancer cells is stabilized by elevated phospholipase D activity and contributes to survival signals generated by phospholipase D. Oncogene. 2006 Nov 23;25(55):7305-10. Epub 2006 Jun 19
  • Arva, N.C., Gopen, T.R., Talbott, K.E., Campbell, L.E., Chicas, A., White, D.E., Bond, G., Levine, A. and J. Bargonetti (2005) A chromatin associated and transcriptionally inactive p53-mdm2 complex occurs in mdm2 SNP309 homozygous cells. J. Biol. Chem. 280(29):26776-87
  • Bond, G.L., W. Hu, E.E. Bond, H. Robins, F. Bartel, H. Taubert, P. Wuerl, K. Onel, L. Yip, S. Hwang, L.C. Strong, N.C. Arva, J. Bargonetti, G. Lozano, and A.J. Levine (2004) A Single Nucleotide Polymorphism in the Mdm2 Promoter Attenuates the p53 Tumor Suppressor Pathway and Accelerates Tumor Formation in Humans. Cell 119:591-602.
  • Abbas, T., D. White, L.Hui, .D.A., Foster and J. Bargonetti (2004) Inhibition of p53 transcription by down-regulation of protein kinase C delta. Journal of Biological Chemistry 279 (11):9970-9977
  • Hui, L., Abbas, T., Bargonetti, J., and D.A. Foster. (2004). Phospholipase D Elevates the Level of MDM2 and Suppresses DNA Damage-Induced Increases in p53. Mol. Cell Biology (24): 5677-5686.
  • Molina, M. P., C. Cain, and J. Bargonetti (2003) In Vivo footprinting and DNA Affinity Chromatography for Analysis of p53 DNA Binding Ability. Methods in Molecular Biology 234:151-70
  • Abbas, T., M. Olivier, J. Lopez,, S. Houser, G. Xiao, G. S. Kumar, M. Tomasz, and J. Bargonetti (2002). Differential activation of p53 by the various adducts of Mitomycin C. Journal of Biological Chemistry 277(43):40513-9.
  • Bargonetti, J. and J.J. Manfredi. (2002). Multiple roles of the tumor suppressor p53. Curr. Opin. Oncology. 14:86-91.
  • Houser, S., S.Koshlatyi , T. Lu , T. Gopen, and J. Bargonetti (2001). Camptothecin and Zeocin Can Differentially Increase p53 Levels During all Cell Cycle Stages. Biochem Biophys Res Commun. 289:998-1009.
  • Chicas, A., P. Molina, and J. Bargonetti (2000). Mutant p53 forms a complex with Sp1 on HIV-LTR DNA. Biochem Biophys Res Commun. 279:383-390.
  • Xiao, G., A. Chicas, M. Olivier, Y. Taya, S. Tyagi, F.R. Kramer and J. Bargonetti, (2000). p53 requires a damage signal to activate gadd45. Cancer Research 60: 1711-1719.
  • Boydston-White, S., T. Gopen, S. Houser, J. Bargonetti and M. Diem, (1999). Infrared spectroscopy of human tissue: V. Infrared Spectroscopic studies of myeloid leukemia (ML-1) cells at different phases of the cell cycle. Biospectroscopy 5: 219-227.
  • Xiao, G., D. White, and J. Bargonetti (1998). p53 binds to a constitutively nucleosome free region of the mdm2 gene. Oncogene 16:1171-1181.
  • Bargonetti, J., A. Chicas, D. White, and C. Prives (1997). p53 represses Sp1 DNA Binding and HIV-LTR directed transcription. Cellular & Molecular Biology 43:935-949.
  • Chen, X., J. Bargonetti, and C. Prives, (1995). p53, through p 21 (WAF1/CIP1), induces cyclin D1 synthesis. Cancer Research 55:4257-4263.
  • Prives, C., J. Bargonetti, G. Farmer, E. Ferrari, P. Friedlander, U. Hubsher, L. Jayaraman, N. Pavletich, and Y. Wang, (1994). The DNA binding properties of the p53 tumor suppressor protein. CSHS on Quan. Bio. LIX:207-213.
  • Bargonetti, J., J.J. Manfredi, X. Chen, D.R. Marshak, and C. Prives, (1993). A proteolytic fragment from the central region of p53 has marked sequence-specific binding activity when generated from wild-type but not from oncogenic mutant p53 protein. Genes and Dev. 7:2565-2574.
  • Bargonetti, J., P.Z. Wang, and R.P. Novick, (1993). Measurement of gene expression by translational coupling: effect of copy mutations on pT181 initiator synthesis. EMBO 12:3659-3667.
  • Friedman, P.N., X. Chen, J. Bargonetti, and C. Prives, (1993). The p53 protein is an unusually shaped tetramer that binds directly to DNA. Proc. Natl. Acad. Sci. USA. 90:3319-3323.
  • Bargonetti, J., I. Reynisdottir, P.N. Friedman, and C. Prives, (1992). Site-specific binding of wild-type p53 to cellular DNA is inhibited by SV40 T antigen and mutant p53. Genes and Dev. 6:1886-1898.
  • Farmer, G., J. Bargonetti, H. Zhu, P. Friedman, R. Prywes, and C. Prives, (1992). Wild-type p53 activates transcription in vitro. Nature 358:83-86.
  • Zambetti, G.P., J. Bargonetti, K. Walker, C. Prives, and A.J. Levine, (1992). Wild-type p53 mediates positive regulation of gene expression through a specific DNA sequence element. Genes and Dev. 6:1143-1152.
  • Prives, C., J. Bargonetti, P.N. Friedman, J.J. Manfredi, and E.H. Wang, (1991). Functional consequences of the interactions of the p53 tumor suppressor protein and SV40 large tumor antigen. CSHS on Quan. Bio. LVL:227-235.
  • Bargonetti, J., P.N. Friedman, S.E. Kern, B. Vogelstein, and C. Prives, (1991). Wild-type but not mutant p53 immunopurified proteins bind to sequences adjacent to the SV40 origin of replication. Cell 65:1083-1091.

Last Updated ( Tuesday, 14 November 2017 21:45 )