Browsing by Subject "Cell Survival"
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Item The Developmental Transcription Factor Neurogenic Differentiation 1 in Migration and Survival of Neuroendocrine Carcinomas(2013-03-12) Osborne, Jihan K.; Minna, John D.; White, Michael A.; Johnson, Jane E.; Cobb, Melanie H.Differentiation and determination of cell fate during embryogenesis is decided by a collection of transcription factors, including the large family of basic-helix-loop-helix (bHLH) transcription factors. Neurogenic differentiation 1 (NeuroD1) is a bHLH transcription factor responsible for neuronal and neuroendocrine islet differentiation during development of the central and peripheral nervous systems and the pancreas respectively. NeuroD1 has also been shown to be anomalously expressed in a subset of aggressive neuroendocrine tumors. Initial examination of microarray data revealed that subsets of aggressive small cell lung cancers (SCLC) and certain neuroendocrine non-small cell lung cancers (NSCLC-NE) have high expression of NeuroD1 as compared to human bronchial epithelial cells (HBEC) and other non-small cell lung cancers (NSCLC). In several neuroendocrine carcinomas, including subsets of neuroendocrine lung cancers, melanoma and some undifferentiated prostate cell lines, NeuroD1 directly induces the expression of signaling pathways that support survival and migration. Loss-of-function/gain-of-function studies in cell lines from each of these cancer types reveled that NeuroD1 regulates both survival and the migration potential of neuroendocrine carcinomas that have lost or mutated p53. Subsequently, loss of p53 has been shown to up-regulate NeuroD1 expression in non-transformed HBECs and cancer cells with neuroendocrine features. The actions of NeuroD1 are carried out by downstream targets which include the signaling molecules, the tyrosine kinase, tropomyosin-related kinase B (TrkB), and the adhesion molecule, neural cell adhesion molecule (NCAM), and the ion channels, the nicotinic acetylcholine receptor subunit cluster of α3, α5, and β4 (nAChR), to name a few. Impaired expression of each of these downstream targets mirrors the various phenotypes associated with loss of NeuroD1. These findings ultimately have implications for the potential of NeuroD1 acting as a lineage-dependent oncogene in neuroendocrine carcinomas.Item p53 in a Genetic Model: Illuminating Adaptive Radiation Responses(2005-05-03) Sogame, Naoko; Abrams, John M.When cells are challenged by genotoxic stress, the tumor suppressor protein p53 promotes adaptive responses, including cell cycle arrest, DNA repair, or apoptosis. How these distinct fates are specified through an action of a single protein is not known. To study its functions in vivo we produced a targeted mutation at the Drosophila p53 (Dmp53) locus. I show that Dmp53 is required for damage-induced apoptosis but not for cell cycle arrest. Dmp53 function is also required for damage-induced transcription of two tightly linked cell death activators, reaper and sickle. When challenged by ionizing radiation, Dmp53 mutants exhibit radiosensitivity and genomic instability, indicating in our model, apoptosis is important for maintenance of genomic stability in response to ionizing radiation. I also examined a global transcriptional change in response to ionizing radiation in the absence of Dmp53. Only 35 genes were constantly radiation responsive in wild type animals and Dmp53 was required for induction of a vast majority of the genes. The Radiation Induced p53 Dependent (RIPD) genes include genes implicated in apoptosis and DNA repair as well as genes with unknown functions. The functional significance of RIPD genes for the activation of apoptosis was tested using RNAi. Thus far, I uncovered ribonucleotide reductase large subunit (RnrL) as a novel Dmp53 target that is necessary for induction of caspase activation. Taken together, my study supports the notion that core ancestral functions of the p53 gene family are intimately coupled to cell death and possibly DNA repair as an adaptive response.