Bargonetti Lab

Jill Bargonetti, Professor of Biological Sciences Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it Office: Room 942 Phone: (212) 650-3519 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 p53, mutant p53, and Mdm2 isoforms  

• ·         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 a more targeted chemotherapeutic approach will be required to result in an outcome of cell death. A focus on such targeted approaches are central to the experiments being carried out in the Bargonetti laboratory.  The work in my laboratory 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 cells. Presently this work is carried out using human cancer cell line models and with a C. elegans nematode model system. Most recently work in my laboratory has characterized that the nucleoside analogue 8-amino-adenosine kills metastatic breast cancers independently of activating the p53-pathway.

  ·       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. We 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. 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 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. We 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 a single nucleotide polymorphism (SNP) at position 309 in the mdm2 gene that causes increased affinity for SP1, leading to Mdm2 overexpression from the gene’s P2 promoter. In cells that have this 309 SNP, the p53 pathway is compromised. High levels of Mdm2 cause increased degradation of p53 protein, however the complexity of the inhibition of p53 by Mdm2 suggests alternative mechanisms for inhibition (and not just degradation) also play a role.

  ·       Awarded the prestigious Presidential Early Career Award for Scientists and Engineers by President Bill Clinton, Bargonetti has received research grants from the National Science Foundation and the National Institutes of Health. She also won a Young Investigator Award, given by the mayor of New York City, the 1998 New York Voice Award, given to those who have made a significant improvement to the quality of life in New York City, and the 1997 Kathy Keeton Mountain Top Award from the New York branch of the NAACP. In December 2004, Working Mother magazine profiled her as one of the nation’s “Stellar Moms.” Most recently Bargonetti has been awarded a Breast Cancer Research Foundation Award for her work on the relationship between Estrogen and the inhibition of the p53 tumor suppressor pathway. 
   

  Selected Publications:  

  ·        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.