ROLES AND REGULATION OF P53

Summary

Principal Investigator: Carol Prives
Abstract: DESCRIPTION (provided by applicant): This is the second renewal of our Program Project that has been in existence for over 10 years and which has been highly productive and interactive. The goals of this program will be realized through an interdisciplinary and collaborative approach to understand the roles of mutant p53, p53 family member's p63 and p73 and new tumor suppressor genes in cancer. Our approaches include cell biology, proteomics, microscopy, bioinformatics, functional genomics, mouse modeling and human and mouse pathology. As this program has progressed, our research has become more translational and relevant to human disease, now focusing on breast, bladder and lymphoma tumor genesis. Carol Prives will employ the 3D culture protocol to examine the roles of mutant p53 and p53 homologues (P63 and p73) in mammary cell morphology and oncogenic transformation. She will also characterize the mechanisms of ANp63 protein turnover in these contexts. Arnold Levine will pursue the observation that breast cancer cells with mutant p53 have a stem cell gene expression signature, and will test mutant p53 allele-specific drugs that were identified by novel bioinformatic approaches for treatment of cancer cells. Levine will also study the roles of SNPs in p63 or p73 that influence DNA repair systems in female eggs and copy number variation that affect cancer in offspring Scott Lowe will continue to study the genetic and molecular basis of lymphoma. He will perform shRNA screens using the Ep-Myc B cell model to identify new tumor suppressor genes. He will also examine the role of genes co-deleted with p53 in lymphoma on chromosome 17p testing the hypothesis that such genes may also have tumor suppressive activity. Additionally Lowe will study the impact of reactivation of latent p53 by down-regulation of Mdm2, as well as perform an shRNA screen to identify genes whose inhibition facilitates death of mutant-p53 dependent tumors. Cordon-Cardo will focus on p63 expression and roles in normal and cancerous bladder tissue in mice and humans. He will use specific shRNAs to characterize the impact of p63 isoforms during urothelial development in mice, and determine the expression of p63 isoforms in bladder carcinoma. Cordon-Cardo will also pursue identification of bladder stem cells and the mechanisms by which they are chemoresistant. This program is highly dependent on the functioning of cores that support the administration, histopathology, shRNAs, mouse modeling and bioinfomatics that is required for the proposed experiments. The projects are even more interdependent and interactive than before and as a result much of the proposed research cannot be done effectively without the support of this program.
Funding Period: 2000-09-30 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. pmc MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia
    Chong Chen
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Cell 25:652-65. 2014
  2. pmc A pipeline for the generation of shRNA transgenic mice
    Lukas E Dow
    Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
    Nat Protoc 7:374-93. 2012
  3. pmc Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway
    William A Freed-Pastor
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Cell 148:244-58. 2012
  4. ncbi Predictive value of microtubule associated proteins tau and stathmin in patients with nonmuscle invasive bladder cancer receiving adjuvant intravesical taxane therapy
    Matthew S Wosnitzer
    Department of Urology, Columbia University College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA
    J Urol 186:2094-100. 2011
  5. pmc Distinct expression profiles of p63 variants during urothelial development and bladder cancer progression
    Orit Karni-Schmidt
    Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA
    Am J Pathol 178:1350-60. 2011
  6. pmc Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures
    Hideaki Mizuno
    The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ 08540, USA
    Proc Natl Acad Sci U S A 107:22745-50. 2010
  7. pmc Association of nuclear localization of a long interspersed nuclear element-1 protein in breast tumors with poor prognostic outcomes
    Chris R Harris
    The Verto Institute, New Brunswick, NJ, USA
    Genes Cancer 1:115-24. 2010
  8. pmc APC/C(Cdc20) targets E2F1 for degradation in prometaphase
    Melissa J Peart
    Department of Biological Sciences, Columbia University, New York, NY, USA
    Cell Cycle 9:3956-64. 2010
  9. pmc Transcriptional regulation by p53
    Rachel Beckerman
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    Cold Spring Harb Perspect Biol 2:a000935. 2010
  10. pmc The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein
    Zhaohui Feng
    Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA
    Trends Cell Biol 20:427-34. 2010

Research Grants

  1. JHU ICMIC PROGRAM
    Zaver M Bhujwalla; Fiscal Year: 2013
  2. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013

Detail Information

Publications50

  1. pmc MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia
    Chong Chen
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Cell 25:652-65. 2014
    ..Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor and suggests a therapeutic option for this aggressive disease. ..
  2. pmc A pipeline for the generation of shRNA transgenic mice
    Lukas E Dow
    Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
    Nat Protoc 7:374-93. 2012
    ..In all, this 14-week procedure provides a fast and cost-effective way for any laboratory to investigate gene function in vivo in the mouse...
  3. pmc Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway
    William A Freed-Pastor
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Cell 148:244-58. 2012
    ..Finally, p53 mutation correlates with highly expressed sterol biosynthesis genes in human breast tumors. These findings implicate the mevalonate pathway as a therapeutic target for tumors bearing mutations in p53...
  4. ncbi Predictive value of microtubule associated proteins tau and stathmin in patients with nonmuscle invasive bladder cancer receiving adjuvant intravesical taxane therapy
    Matthew S Wosnitzer
    Department of Urology, Columbia University College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA
    J Urol 186:2094-100. 2011
    ....
  5. pmc Distinct expression profiles of p63 variants during urothelial development and bladder cancer progression
    Orit Karni-Schmidt
    Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA
    Am J Pathol 178:1350-60. 2011
    ..This study highlights the relevance of p63 isoforms in both urothelial development and bladder carcinoma progression, with ΔNp63 acting as an oncogene in certain invasive bladder tumors...
  6. pmc Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures
    Hideaki Mizuno
    The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ 08540, USA
    Proc Natl Acad Sci U S A 107:22745-50. 2010
    ..These data are consistent with a model in which loss of p53 function enables acquisition of stem cell properties, which are positively selected during tumor progression...
  7. pmc Association of nuclear localization of a long interspersed nuclear element-1 protein in breast tumors with poor prognostic outcomes
    Chris R Harris
    The Verto Institute, New Brunswick, NJ, USA
    Genes Cancer 1:115-24. 2010
    ..High expression and nuclear localization of L1-ORF1p may result in a higher rate of L1 retrotransposition, which could increase genomic instability...
  8. pmc APC/C(Cdc20) targets E2F1 for degradation in prometaphase
    Melissa J Peart
    Department of Biological Sciences, Columbia University, New York, NY, USA
    Cell Cycle 9:3956-64. 2010
    ..These data suggest that APC/C(Cdc20) specifically targets E2F1 for degradation in early mitosis and reveal a novel mechanism for limiting free E2F1 levels in cells, failure of which may compromise cell survival and/or homeostasis...
  9. pmc Transcriptional regulation by p53
    Rachel Beckerman
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    Cold Spring Harb Perspect Biol 2:a000935. 2010
    ..How p53 is able to discriminate between these different loci is the subject of intense research. Here, we describe key aspects of the fundamentals of p53-mediated transcriptional regulation and target gene promoter selectivity...
  10. pmc The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein
    Zhaohui Feng
    Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA
    Trends Cell Biol 20:427-34. 2010
    ..The use of these alternative metabolic pathways is an integral part of both normal and oncogenic phenotypes...
  11. pmc Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function
    Wenwei Hu
    Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA
    Proc Natl Acad Sci U S A 107:7455-60. 2010
    ..These results demonstrated that as a unique p53 target gene, GLS2 is a mediator of p53's role in energy metabolism and antioxidant defense, which can contribute to its role in tumor suppression...
  12. pmc A BAC-based transgenic mouse specifically expresses an inducible Cre in the urothelium
    Tian Huai Shen
    Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America
    PLoS ONE 7:e35243. 2012
    ....
  13. pmc Targeting synthetic lethal interactions between Myc and the eIF4F complex impedes tumorigenesis
    Chen Ju Lin
    Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada
    Cell Rep 1:325-33. 2012
    ..Therefore, eIF4F is a key Myc client that represents a tumor-specific vulnerability...
  14. pmc Allele-specific p53 mutant reactivation
    Xin Yu
    The Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
    Cancer Cell 21:614-25. 2012
    ..This activity depends upon the zinc ion chelating properties of the compound as well as redox changes. These data identify NSC319726 as a p53(R175) mutant reactivator and as a lead compound for p53-targeted drug development...
  15. pmc Suppression of eukaryotic initiation factor 4E prevents chemotherapy-induced alopecia
    Zeina Nasr
    Departments of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada
    BMC Pharmacol Toxicol 14:58. 2013
    ..Proof-of-concept for this approach, known as cyclotherapy, has been demonstrated in cell culture settings...
  16. pmc RNAi screening uncovers Dhx9 as a modifier of ABT-737 resistance in an Eμ-myc/Bcl-2 mouse model
    John R Mills
    Department of Biochemistry McGill University, Montreal, Quebec, Canada
    Blood 121:3402-12. 2013
    ..Rather, loss of Dhx9 appeared to activate a p53-dependent apoptotic program, through aggravation of replicative stress, which was found to be both necessary and sufficient for the ABT-737-shDhx9 synthetic lethal relationship...
  17. pmc A common MicroRNA signature consisting of miR-133a, miR-139-3p, and miR-142-3p clusters bladder carcinoma in situ with normal umbrella cells
    Angela Y Jia
    Department of Pathology and Cell Biology, Columbia University, New York, New York, USA
    Am J Pathol 182:1171-9. 2013
    ..Notably, this study provides evidence of the possible origin relationship between CIS and normal umbrella cells...
  18. pmc The Interfaces Between Signal Transduction Pathways: IGF-1/mTor, p53 and the Parkinson Disease Pathway
    Arnold J Levine
    Cancer Institute of New Jersey, UMDNJ, New Brunswick, N J
    Oncotarget 3:1301-7. 2012
    ..These interaction sites of the IGF/mTOR-p53- Parkinson genes pathways are reviewed with a focus upon a common role of responding to the generation of reactive oxygen species and mitophagy...
  19. pmc Proliferation and tissue remodeling in cancer: the hallmarks revisited
    E K Markert
    The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA
    Cell Death Dis 3:e397. 2012
    ..Notably, the proliferation signature correlates with poor outcome in lung, prostate, breast and brain cancer, whereas remodeling increases mortality rates in colorectal and ovarian cancer...
  20. pmc Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer
    Paola Tucci
    Medical Research Council, Toxicology Unit, Leicester University, Leicester, United Kingdom
    Proc Natl Acad Sci U S A 109:15312-7. 2012
    ..These data suggest that p63/miR-205 may be a useful clinical predictor of metastatic behavior in prostate cancer...
  21. pmc Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53
    Megan J Bywater
    Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia
    Cancer Cell 22:51-65. 2012
    ..These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies...
  22. pmc A tumour suppressor network relying on the polyamine-hypusine axis
    Claudio Scuoppo
    Watson School of Biological Sciences, Cold Spring Harbor Laboratory, New York 11724, USA
    Nature 487:244-8. 2012
    ..Thus, some tumour suppressor functions can be disabled through a two-step process targeting different genes acting in the same pathway...
  23. pmc Mutant p53: one name, many proteins
    William A Freed-Pastor
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    Genes Dev 26:1268-86. 2012
    ..Here we review mechanisms by which mutant p53 exerts its cellular effects, with a particular focus on the burgeoning mutant p53 transcriptome, and discuss the biological and clinical consequences of mutant p53 gain of function...
  24. pmc Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species
    Sawako Suzuki
    Department of Clinical Cell Biology and Division of Endocrinology and Metabolism, Chiba University Graduate School of Medicine, Chiba shi, Chiba 260 8670, Japan
    Proc Natl Acad Sci U S A 107:7461-6. 2010
    ..Thus, our results provide evidence for a unique metabolic role for p53, linking glutamine metabolism, energy, and ROS homeostasis, which may contribute to p53 tumor suppressor function...
  25. pmc TAp63 induces senescence and suppresses tumorigenesis in vivo
    Xuecui Guo
    Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
    Nat Cell Biol 11:1451-7. 2009
    ..The ability of TAp63 to trigger senescence and halt tumorigenesis irrespective of p53 status identifies TAp63 as a potential target of anti-cancer therapy for human malignancies with compromised p53...
  26. pmc Dissecting eIF4E action in tumorigenesis
    Hans Guido Wendel
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Genes Dev 21:3232-7. 2007
    ..Our results provide insight into how eIF4E contributes to tumorigenesis and pinpoint a level of translational control that may be suitable for therapeutic intervention...
  27. pmc Declining p53 function in the aging process: a possible mechanism for the increased tumor incidence in older populations
    Zhaohui Feng
    Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA
    Proc Natl Acad Sci U S A 104:16633-8. 2007
    ....
  28. ncbi Energy-dependent nucleolar localization of p53 in vitro requires two discrete regions within the p53 carboxyl terminus
    O Karni-Schmidt
    Department of Biological Sciences, Columbia University, New York, USA
    Oncogene 26:3878-91. 2007
    ..The possible significance of these findings is discussed...
  29. pmc The Mdm2 RING domain C-terminus is required for supramolecular assembly and ubiquitin ligase activity
    Masha V Poyurovsky
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    EMBO J 26:90-101. 2007
    ..We further show that the Mdm2 C-terminus is involved in intramolecular interactions and can set up a platform for direct protein-protein interactions with the E2...
  30. pmc p53 and p73 display common and distinct requirements for sequence specific binding to DNA
    Maria Lokshin
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Nucleic Acids Res 35:340-52. 2007
    ....
  31. ncbi Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo
    Hans Guido Wendel
    Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
    Cancer Res 66:7639-46. 2006
    ..Understanding these genotype-response relationships in human tumors will be important for the effective use of rapamycin or other compounds targeting the PI(3)K pathway in the clinic...
  32. pmc MDM2 SNP309 accelerates colorectal tumour formation in women
    Gareth L Bond
    J Med Genet 43:950-2. 2006
    ....
  33. pmc Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach
    Lars Zender
    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
    Cell 125:1253-67. 2006
    ..Our results establish a tractable model of liver cancer, identify two oncogenes that cooperate by virtue of their coamplification in the same genomic locus, and suggest an efficient strategy for the annotation of human cancer genes...
  34. ncbi MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner
    Gareth L Bond
    The Institute for Advanced Study, Princeton, New Jersey 08540, USA
    Cancer Res 66:5104-10. 2006
    ....
  35. pmc Loss of p53 impedes the antileukemic response to BCR-ABL inhibition
    Hans Guido Wendel
    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
    Proc Natl Acad Sci U S A 103:7444-9. 2006
    ..Our results identify p53 as a determinant of the response to oncogene inhibition and suggest one way in which resistance to targeted therapy can emerge during the course of tumor evolution...
  36. pmc Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model
    Marie Eve Bordeleau
    Department of Biochemistry, McGill University, Montreal, Quebec, Canada
    J Clin Invest 118:2651-60. 2008
    ..These results establish that targeting translation initiation can restore drug sensitivity in vivo and provide an approach to modulating chemosensitivity...
  37. pmc mTORC1 promotes survival through translational control of Mcl-1
    John R Mills
    Department of Biochemistry, McGill University, Montreal, QC, Canada H3G 1Y6
    Proc Natl Acad Sci U S A 105:10853-8. 2008
    ..Our results indicate that the extent by which rapamycin can modulate expression of Mcl-1 is an important feature of the rapamycin response...
  38. pmc Tumorigenic activity and therapeutic inhibition of Rheb GTPase
    Konstantinos J Mavrakis
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Genes Dev 22:2178-88. 2008
    ..Of these, only eIF4E was able to enhance lymphomagenesis in vivo. In summary, the Rheb GTPase is an oncogenic activity upstream of mTORC1 and eIF4E and a direct therapeutic target of farnesyltransferase inhibitors in cancer...
  39. pmc The first 30 years of p53: growing ever more complex
    Arnold J Levine
    Arnold J Levine is at the Institute for Advanced Study, School of Natural Sciences, Einstein Drive, Princeton, New Jersey 08540, USA
    Nat Rev Cancer 9:749-58. 2009
    ..The fourth decade of research may see new p53-based drugs to treat cancer. What is next is anybody's guess...
  40. pmc p53 responsive elements in human retrotransposons
    C R Harris
    Raymond and Beverly Sackler Foundation, New Brunswick, NJ 08540, USA
    Oncogene 28:3857-65. 2009
    ....
  41. pmc A role for Chk1 in blocking transcriptional elongation of p21 RNA during the S-phase checkpoint
    Rachel Beckerman
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    Genes Dev 23:1364-77. 2009
    ..These findings demonstrate for the first time a link between the replication checkpoint mediated by ATR/Chk1 and the transcription elongation/3' processing machinery...
  42. pmc Stxbp4 regulates DeltaNp63 stability by suppression of RACK1-dependent degradation
    Yingchun Li
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Mol Cell Biol 29:3953-63. 2009
    ..Upon genotoxic stress, however, Stxbp4 itself is downregulated, correlating with DeltaNp63 destabilization mediated in part by RACK1. Taken together, we have delineated key mechanisms that regulate DeltaNp63 protein stability in vivo...
  43. pmc Inactivation of p53 and Pten promotes invasive bladder cancer
    Anna M Puzio-Kuter
    Department of Urology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA
    Genes Dev 23:675-80. 2009
    ..Our integrated analyses of mouse and human bladder cancer provide a rationale for investigating mTOR inhibition for treatment of patients with invasive disease...
  44. ncbi p53 is localized to a sub-nucleolar compartment after proteasomal inhibition in an energy-dependent manner
    Orit Karni-Schmidt
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    J Cell Sci 121:4098-105. 2008
    ..Importantly, we demonstrate that p53 nucleolar association occurs in lung and bladder carcinomas...
  45. pmc An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer
    Lars Zender
    Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
    Cell 135:852-64. 2008
    ..Our results establish the feasibility of in vivo RNAi screens and illustrate how combining cancer genomics, RNA interference, and mosaic mouse models can facilitate the functional annotation of the cancer genome...
  46. pmc Lysine-independent turnover of cyclin G1 can be stabilized by B'alpha subunits of protein phosphatase 2A
    Hongyun Li
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    Mol Cell Biol 29:919-28. 2009
    ..Our results thus indicate that proteasomal turnover of cyclin G1 is regulated by noncanonical processes...
  47. ncbi Excess HDM2 impacts cell cycle and apoptosis and has a selective effect on p53-dependent transcription
    Shuichi Ohkubo
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    J Biol Chem 281:16943-50. 2006
    ..Thus, HDM2 can selectively down-regulate the transcription function of p53 without either degrading p53 or affecting the interaction of p53 with target promoters...

Research Grants30

  1. JHU ICMIC PROGRAM
    Zaver M Bhujwalla; Fiscal Year: 2013
    ..The Career Development Component is structured with the purpose of creating independently funded investigators who will, in the future, become leaders in the field. ..
  2. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....