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Author (up) Culmsee, C.; Mattson, M.P. file  url
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  Title p53 in neuronal apoptosis Type Journal Article
  Year 2005 Publication Biochemical and Biophysical Research Communications Abbreviated Journal Biochem Biophys Res Commun  
  Volume 331 Issue 3 Pages 761-777  
  Keywords Animals; Apoptosis/*physiology; Apoptosis Regulatory Proteins; DNA Damage; Gene Expression Regulation; Humans; Neurodegenerative Diseases/*physiopathology; Neurons/*cytology/*physiology; Nuclear Proteins/physiology; Proto-Oncogene Proteins/physiology; Proto-Oncogene Proteins c-bcl-2/physiology; Proto-Oncogene Proteins c-mdm2; Synapses/physiology; Transcriptional Activation; Tumor Suppressor Protein p53/*physiology; bcl-2-Associated X Protein  
  Abstract The tumor suppressor and transcription factor p53 is a key modulator of cellular stress responses, and activation of p53 can trigger apoptosis in many cell types including neurons. Apoptosis is a form of programmed cell death that occurs in neurons during development of the nervous system and may also be responsible for neuronal deaths that occur in neurological disorders such as stroke, and Alzheimer's and Parkinson's diseases. p53 production is rapidly increased in neurons in response to a range of insults including DNA damage, oxidative stress, metabolic compromise, and cellular calcium overload. Target genes induced by p53 in neurons include those encoding the pro-apoptotic proteins Bax and the BH3-only proteins PUMA and Noxa. In addition to such transcriptional control of the cell death machinery, p53 may more directly trigger apoptosis by acting at the level of mitochondria, a process that can occur in synapses (synaptic apoptosis). Preclinical data suggest that agents that inhibit p53 may be effective therapeutics for several neurodegenerative conditions.  
  Call Number Serial 2167  
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Author (up) Prabhu, V.V.; Hong, B.; Allen, J.E.; Zhang, S.; Lulla, A.R.; Dicker, D.T.; El-Deiry, W.S. file  url
openurl 
  Title Small-Molecule Prodigiosin Restores p53 Tumor Suppressor Activity in Chemoresistant Colorectal Cancer Stem Cells via c-Jun-Mediated DeltaNp73 Inhibition and p73 Activation Type Journal Article
  Year 2016 Publication Cancer Research Abbreviated Journal Cancer Res  
  Volume 76 Issue 7 Pages 1989-1999  
  Keywords p53; Tumor suppression; p73; Colorectal cancer; Stem cells  
  Abstract Tumor suppressor p53 is frequently mutated or inactivated in colorectal cancer. In contrast, p53 family member p73 is rarely mutated in colorectal cancer and p73 activation elicits p53-like tumor suppression. Colorectal cancer stem cells (CRCSC) comprise a rare self-renewing subpopulation that contributes to tumor maintenance and chemoresistance. p53 restoration is known to target CRCSCs, but p73 restoration in CRCSCs has not been examined. In this study, we investigated the effects of the small-molecule prodigiosin, which restores the p53 pathway in tumor cells via p73 activation, on CRCSCs in vitro and in vivo Prodigiosin prevented colonosphere formation independent of p53 status and reduced the viability of self-renewing, 5-fluorouracil-resistant Aldefluor positive [Aldefluor(+)] CRCSCs in vitro Furthermore, prodigiosin inhibited the growth of xenograft tumors initiated with Aldefluor+ cells without toxic effects and limited the tumorigenic potential of these cells. Consistently, prodigiosin induced activation of a p53-responsive luciferase reporter in colonospheres, Aldefluor(+) cells, and tumor xenografts. Mechanistic studies revealed that prodigiosin increased the levels of p73 and reduced levels of the oncogenic N-terminally truncated isoform DeltaNp73 in Aldefluor(+) cells. Accordingly, p73 knockdown or DeltaNp73 overexpression suppressed prodigiosin-mediated inhibition of colonosphere formation. Moreover, prodigiosin increased levels of the transcription factor c-Jun, a regulator of p73 and DeltaNp73, in both the cytoplasm and nucleus. c-Jun knockdown attenuated prodigiosin-mediated p53-reporter activation, DeltaNp73 downregulation, p73 activation, and cell death. Collectively, our findings highlight the previously uncharacterized use of p73-activating therapeutics to target CRCSCs.  
  Call Number Serial 1518  
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Author (up) Sahin, I.H.; Iacobuzio-Donahue, C.A.; O'Reilly, E.M. file  url
openurl 
  Title Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy Type Journal Article
  Year 2016 Publication Expert Opinion on Therapeutic Targets Abbreviated Journal Expert Opin Ther Targets  
  Volume 20 Issue 3 Pages 341-359  
  Keywords K-Ras pathway; Wnt signaling; cancer stem cells; expression signature; molecular pathways; notch signaling; p53; pancreatic cancer; targeted treatment  
  Abstract INTRODUCTION: Pancreatic adenocarcinoma remains one of the most clinically challenging cancers despite an in-depth characterization of the molecular underpinnings and biology of this disease. Recent whole-genome-wide studies have elucidated the diverse and complex genetic alterations which generate a unique oncogenic signature for an individual pancreatic cancer patient and which may explain diverse disease behavior in a clinical setting. AREAS COVERED: In this review article, we discuss the key oncogenic pathways of pancreatic cancer including RAS-MAPK, PI3KCA and TGF-beta signaling, as well as the impact of these pathways on the disease behavior and their potential targetability. The role of tumor suppressors particularly BRCA1 and BRCA2 genes and their role in pancreatic cancer treatment are elaborated upon. We further review recent genomic studies and their impact on future pancreatic cancer treatment. EXPERT OPINION: Targeted therapies inhibiting pro-survival pathways have limited impact on pancreatic cancer outcomes. Activation of pro-apoptotic pathways along with suppression of cancer-stem-related pathways may reverse treatment resistance in pancreatic cancer. While targeted therapy or a 'precision medicine' approach in pancreatic adenocarcinoma remains an elusive challenge for the majority of patients, there is a real sense of optimism that the strides made in understanding the molecular underpinnings of this disease will translate into improved outcomes.  
  Call Number Serial 1505  
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Author (up) Zhan, Q.; Fan, S.; Bae, I.; Guillouf, C.; Liebermann, D.A.; O'Connor, P.M.; Fornace, A.J.J. file  url
openurl 
  Title Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis Type Journal Article
  Year 1994 Publication Oncogene Abbreviated Journal Oncogene  
  Volume 9 Issue 12 Pages 3743-3751  
  Keywords Apoptosis/*genetics; Gene Expression Regulation/*drug effects/genetics/radiation effects; *Genes, p53; Humans; Mutagens/*toxicity; Neoplasms/genetics; Proto-Oncogene Proteins/*genetics; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured; bcl-2-Associated X Protein  
  Abstract DNA-damaging agents such as ionizing radiation (IR) activate the tumor suppressor p53 and in some cases can cause apoptosis. M1 cells, which do not express the endogenous tumor suppressor gene p53, undergo apoptosis following activation of a temperature sensitive p53 transgene, where it has been shown that bax, an important mediator of apoptosis, is a p53 target gene (Selvakumaran et al, Oncogene 9, 1791-8, 1994). Since p53 can function as a transcription factor after activation by IR, the genetic response to this stress was examined in a panel of human cells with defined p53 status. Like the p53-regulated gene gadd45, bax was rapidly induced, as measured by increased mRNA levels, in the p53 wt (wild type) human myeloid line ML-1, and it was not induced in cells lacking functional p53. However, unlike other p53-regulated genes, bax was only induced in p53 wt cells in which IR also triggered apoptosis. In the case of bcl2, which opposes bax function, mRNA levels were reduced in ML-1 cells after IR. Thus, bax appears to be an unique p53-regulated gene in that its induction by IR not only requires functional p53 but also requires that the cells be apoptosis “proficient.”  
  Call Number Serial 2172  
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