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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 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 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 mutant p53, Mdm2, and MdmX molecular signal transduction pathways and we work to activate p53-independent cell death pathways that facilitate killing resistant cancer types. Presently this work is carried out using human cancer cell line models, xenograft models, and C. elegans nematode models.  The Bargonetti research team is using genetically engineered tools to decrease expression of and/or mutate the 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.

Project 1: Oncogenic Gain-of-function (GOF) Mutant p53.
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. We discovered of a set of interactions between mutant p53 (mtp53), PARP, and MCMs on chromatin that may elucidate at least one aspect of gain-of-function (GOF) mtp53. In addition, we observed that high mtp53 and PARP sensitize cells to PARP inhibitors (PARPi) plus DNA damage, suggesting a therapeutic targeting approach. In addition, we observed that high mtp53 and PARP sensitize cells to PARP inhibitors (PARPi) plus DNA damage, suggesting a therapeutic targeting approach. We are currently working on projects that address the mechanistic role of GOF mtp53 at replication forks and how mtp53 helps to recruit replication factors.

Project 2: MDM2 and MDMX p53-independent oncogenic roles in breast cancer..
We discovered that reducing the amount of Mdm2 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.  Our work has been instrumental for introducing the concept of an estrogen driven signaling pathway that uses a non-canonical Mdm2 molecular mechanism. We are dissecting the relevant targets of Mdm2 and MdmX in different subtypes of breast cancer. We recently discovered that both Mdm2 and MdmX promote triple negative breast cancer metastasis (TNBC). We are currently addressing if blocking the Mdm2 and MdmX proteins with pharmacological agents can inhibit TNBC metastasis. The Bargonetti group also 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.

Project 3: The roles of Mutant C. elegans p53 1 (CEP1) in hyperproliferative germline and worm lifespan.
Undergraduate students are invited to register for Introduction to Experimental Biology to get college credits for working on this C. elegans project. This is a genetics and cell biology experimental cell biology project.

  

Jill Bargonetti received her B.A. from SUNY Purchase, her M.S. and Ph.D. from New York University and her postgraduate training from Columbia University. While in the Purchase Dance Corps she performed works by Sarah Stackhouse and Paul Taylor and then went on to became a member of Dianne McIntyre’s Sounds in Motion from 1983-1985. In 1994 she became as an Assistant Professor at The City University of New York (CUNY) at Hunter College and The Graduate Center in the PhD Programs of Biology and Biochemistry and currently holds the title of Full Professor with tenure. 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 (NSF), The National Institutes of Health (NIH), and the Breast Cancer Research Foundation (BCRF). She was a member of the National Cancer Policy Board from 2002 until 2005 (a board of the Institution of Medicine and National Research Council of the National Academies) and served on the NIH Tumor Cell Biology study section from 2012-2018.  She is currently a reviewer for American Association of Cancer Research grants and reviews manuscripts for numerous high impact journals.

 

Choreographing Genomics: Her understandings on the unifying principles of dance, genomics, and cancer inspire her work.

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

  • , G.K., Elshabassy, N., Lundine, D., Conde, D-G., Xiao, G., Ellison, V.,and Bargonetti, J., Frame-shift Mediated Reduction of Gain-of-function p53 R273H and Oligomerization of Mutant p53 R273H is Not Required for Gain-of-Function Chromatin Associated Activities Frontiers in Cell and Development Biology 2021 November 22: https://doi.org/10.3389/fcell.2021.772315
  • Wilson, T. Pirovano, G., Xiao, G., Samuels, Z., Roberts,S., Viray, T., Guru, N., Zanzonico, P., Gollub, M., Reiner, T., and Bargonetti, J., PARP Targeted Auger Therapy in p53 Mutant Colon Cancer Xenograft Mouse Models. ACS Molecular Pharmaceutics 2021 July 28 online first PMID: 34318678.
  • Ellison, V., Annor, G.K., Freedman, C., Xiao, G., Lundine, D., Freulich, E., Prives, C., and Bargonetti, J., Frame-shift Mediated Reduction of Gain-of-function p53 R273H and Deletion of the R273H C-terminus in Breast Cancer Cells Result in Replication-Stress Sensitivity. Oncotarget 2021 June 8: 12 (12):1128-1146 PMID: 34136083
  • , Jill. “How Choreostorming Informs Thinking In Molecular Genetics And Cancer Biology” Leonardo MIT Press March 11, 2021 doi: 10.1162/LEON_a_02053
  • Xiao G, Annor GK, Fung K, Keinänen O, Zeglis BM, Bargonetti J. Targeting Triple Negative Breast Cancer with a Nucleus-Directed p53 Tetramerization Domain Peptide. Mol Pharm. 2020 Dec 8. doi: 10.1021/acs.molpharmaceut.0c00978. Online ahead of print.PMID: 33289569 https://pubmed.ncbi.nlm.nih.gov/33289569/
  • Kim JY, Lee R, Xiao G, Forbes D, Bargonetti J.MDM2-C Functions as an E3 Ubiquitin Ligase. Cancer Manag Res. 2020 Aug 24;12:7715-7724. doi: 10.2147/CMAR.S260943. eCollection 2020.PMID: 32904724 Free PMC article.https://pubmed.ncbi.nlm.nih.gov/32904724/
  • Farooqi K, Ghazvini M, Pride LD, Mazzella L, White D, Pramanik A, Bargonetti JA Protein in the Yeast Saccharomyces cerevisiae Presents DNA Binding Homology to the p53 Checkpoint Protein and Tumor Suppressor. , Moore CW.Biomolecules. 2020 Mar 7;10(3):417. doi: 10.3390/biom10030417.PMID: 32156076 Free PMC article.https://pubmed.ncbi.nlm.nih.gov/32156076/
  • Xiao G., Lundine D, Annor GK, Canar J, Ellison V, Polotskaia A, Donabedian PL, Reiner T, Khramtsova GFGain-of-Function Mutant p53 R273H Interacts with Replicating DNA and PARP1 in Breast Cancer. , Olopade OI, Mazo A, Bargonetti J.Cancer Res. 2020 Feb 1;80(3):394-405. doi: 10.1158/0008-5472.CAN-19-1036. Epub 2019 Nov 27.PMID: 31776133 Free PMC article.https://pubmed.ncbi.nlm.nih.gov/31776133/
  • Gao C, Xiao G, Bargonetti J. Contemplations on MDMX (MDM4) driving triple negative breast cancer circulating tumor cells and metastasis. Oncotarget. 2019 Aug 20;10(49):5007-5010. doi: 10.18632/oncotarget.27134. eCollection 2019 Aug 20.PMID: 31489110 Free PMC article.https://pubmed.ncbi.nlm.nih.gov/31489110/
  • Bargonetti J, Prives C.J Gain-of-function mutant p53: history and speculation. Mol Cell Biol. 2019 Jul 19;11(7):605-609. doi: 10.1093/jmcb/mjz067.PMID: 31283823 Free PMC article. Review. https://pubmed.ncbi.nlm.nih.gov/31283823/
  • Gao, C., Xiao, G. Piersigilli, A., Gou, J. Ogunwobi, O. and Bargonetti, J. Context Dependent Roles of MDMX (MDM4) and MDM2 in Breast Cancer Proliferation and Circulating Tumor Cells. Breast Cancer Research, 2019 Jan 14;21(1):5 PMID:30642351
  • Loo, L.W.M., Hernandez, B. Y., Shvetsov, Y., Okoro, D. R., Gao, C. and Bargonetti, J. MDM2, MDM2-C, and Mutant p53, Expression Influence Breast Cancer Survival in a Multiethnic Population, Breast Cancer Research and Treatment 2018 Nov 23. PMID: 30470976
  • 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. 
  • 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.

 

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Last Updated ( Friday, 15 April 2022 17:35 )