Education
B.A., 1985 SUNY College at Purchase
Ph.D., 1990 New York University
Postdoc., 1990-1994 Columbia University
Research Interest
DNA damage signaling to p53 and Mdm2
Jill Bargonetti and her laboratory group are currently working to determine if DNA damage caused by various chemotherapeutic drugs (alone and in combination) are able to bring about differential activation of the p53 target genes as well as activate alternative cell death pathways. Mitomycin C (MC) and 10-decarbamoyl MC (DMC) signal to the p53 pathway and other pathways. The group has found that DMC initiates stronger cell death in the absence of p53 than does MC and doesn’t involve p53 family member proteins. The DMC activated p53 independent cell death pathway has hallmarks of apoptosis but lacks caspase activation indicating a novel pathway for which the laboratory has begun to identify the members. The Bargonetti research group investigates how the oncogenic protein Mdm2 functions in multiple ways to inactivate p53 function in cancer cells. In addition her research group has reported a novel finding that tumor promoting chemicals influence the transcription of the p53 gene and that this finding may provide information on how environment chemicals could influence the p53 pathway.
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. 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. The p53 protein is maintained at low levels in normally dividing cells in part through its interaction with Mdm2. However Mdm2 also inhibits the trans-activation function of p53 when the two proteins form a complex. The Bargonetti group recently showed that such functional inhibition occurs by a chromatin associated Mdm2-p53 complex in 309 SNP homozygous cells.
Breast cancer is associated with high levels of expression of the estrogen receptor and the epidermal growth factor receptor. Estrogen receptor positive cells show increased Mdm2 protein expression in the presence of estrogen and this most likely functions to inactivate the p53 checkpoint. The mechanism of this inhibition has not been determined. Work is now emerging from the Bargonetti laboratory that suggests Estrogens can influence the p53 pathway through up regulation of Mdm2 protein and down-regulation of the p53 gene. The Bargonetti group has shown that the well defined tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) blocks the DNA damage mediated activation of the wild-type p53 apoptotic pathway by inhibiting protein kinase C (PKC) delta causing inhibition of basal p53 gene transcription. This suggests that other tumor promoters (like estrogen and epidermal growth factor) function in a similar way. It has been shown that in the estrogen receptor positive MCF7 human breast cancer cell line, treatment with estrogen for 7 days specifically down-regulates PKC delta.
Awarded the prestigious Presidential Early Career Award for Scientists and Engineers by President Bill Clinton, Bargonetti-Chavarria has received research grants from the National Science Foundation and the National Institutes of Health. She also won the 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
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
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
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.
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.
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.
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.
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