Project 2: Functions of the p53 Family of Genes Arnold Levine, Ph.D. The first goal of this project is to explore the role of p53 in regulating the production of cancer stem cells and induced pluripotent stem cells (iPS). It has been shown that the absence of p53 increases the efficiency of production, reduces the time for production, and eliminates the requirement of two oncogenic transcription factors (myc and KLF-4) as fibroblasts are reprogrammed into IPS cells in culture. We have demonstrated that the loss of wild type p53 functions in cancer cells favors the reprogramming of transcriptional signatures so that cancer cells resemble embryonic stem cells and iPS cells. We are exploring the mechanisms involved in this process of cancer stem cell formation. A set of small molecular weight compounds have been identified that act in the nanomolar range as allele specific synthetic lethal drugs when applied to cells with a p53 codon 175 mutation. These drugs induce apoptosis in codon 175 containing cells, but do not act upon cells with wild type p53, and inhibit cell growth to a lesser extent in cells with other p53 mutant alleles. We are exploring the mechanism of action of this drug. Single nucleotide polymorphisms in the p63 and p73 genes of humans have been identified that act in meiosis of the parents but have phenotypes in the offspring: maternal and paternal effect genes. The phenotypes in the offspring result in higher recombination frequencies, increased copy number variations and aneuploidy. We are employing data bases to determine if such mutations in the offspring can cause cancer at young ages and uncover new tumor suppressor genes.
Maternal and paternal effect genes have been identified that can be passed down to children that possibly may be involved in the development of cancer. We are employing data bases to determine if such mutations in the offspring can cause cancer at young ages and uncover new tumor suppressor genes.
| Rokudai, Susumu; Li, Yingchun; Otaka, Yukihiro et al. (2018) STXBP4 regulates APC/C-mediated p63 turnover and drives squamous cell carcinogenesis. Proc Natl Acad Sci U S A 115:E4806-E4814 |
| Rastogi, Chaitanya; Rube, H Tomas; Kribelbauer, Judith F et al. (2018) Accurate and sensitive quantification of protein-DNA binding affinity. Proc Natl Acad Sci U S A 115:E3692-E3701 |
| Baugh, Evan H; Ke, Hua; Levine, Arnold J et al. (2018) Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ 25:154-160 |
| Agmon, Eran; Solon, Jérôme; Bassereau, Patricia et al. (2018) Modeling the effects of lipid peroxidation during ferroptosis on membrane properties. Sci Rep 8:5155 |
| Yozwiak, Carrie E; Hirschhorn, Tal; Stockwell, Brent R (2018) Toward a Microparticle-Based System for Pooled Assays of Small Molecules in Cellular Contexts. ACS Chem Biol 13:761-771 |
| Hirschhorn, Tal; Stockwell, Brent R (2018) The development of the concept of ferroptosis. Free Radic Biol Med : |
| Liu, Hengrui; Schreiber, Stuart L; Stockwell, Brent R (2018) Targeting Dependency on the GPX4 Lipid Peroxide Repair Pathway for Cancer Therapy. Biochemistry 57:2059-2060 |
| Conrad, Marcus; Kagan, Valerian E; Bayir, Hülya et al. (2018) Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev 32:602-619 |
| Zhang, Yan; Larraufie, Marie-Hélène; Musavi, Leila et al. (2018) Design of Small Molecules That Compete with Nucleotide Binding to an Engineered Oncogenic KRAS Allele. Biochemistry 57:1380-1389 |
| Shimada, Kenichi; Reznik, Eduard; Stokes, Michael E et al. (2018) Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells. Cell Chem Biol 25:585-594.e7 |
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