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.
|Otaka, Yukihiro; Rokudai, Susumu; Kaira, Kyoichi et al. (2017) STXBP4 Drives Tumor Growth and Is Associated with Poor Prognosis through PDGF Receptor Signaling in Lung Squamous Cell Carcinoma. Clin Cancer Res 23:3442-3452|
|Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Martín-Martín, Natalia et al. (2017) mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 547:109-113|
|Agmon, Eran; Stockwell, Brent R (2017) Lipid homeostasis and regulated cell death. Curr Opin Chem Biol 39:83-89|
|Kastenhuber, Edward R; Lowe, Scott W (2017) Putting p53 in Context. Cell 170:1062-1078|
|Levine, Arnold J; Berger, Shelley L (2017) The interplay between epigenetic changes and the p53 protein in stem cells. Genes Dev 31:1195-1201|
|Stockwell, Brent R; Friedmann Angeli, José Pedro; Bayir, Hülya et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171:273-285|
|Kribelbauer, Judith F; Laptenko, Oleg; Chen, Siying et al. (2017) Quantitative Analysis of the DNA Methylation Sensitivity of Transcription Factor Complexes. Cell Rep 19:2383-2395|
|Vabret, Nicolas; Bhardwaj, Nina; Greenbaum, Benjamin D (2017) Sequence-Specific Sensing of Nucleic Acids. Trends Immunol 38:53-65|
|Badal, Brateil; Solovyov, Alexander; Di Cecilia, Serena et al. (2017) Transcriptional dissection of melanoma identifies a high-risk subtype underlying TP53 family genes and epigenome deregulation. JCI Insight 2:|
|Hayano, M; Yang, W S; Corn, C K et al. (2016) Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ 23:270-8|
Showing the most recent 10 out of 133 publications