The Transcriptional Program following p53 Activation

Zhao, Renbin; Gish, Kurt; Murphy, Maureen E.; Yin, Yuxin; Notterman, Daniel A.; Hoffman, William H.; Tom, Edward; Mack, David H.; Levine, Arnold J.

doi:10.1101/sqb.2000.65.475

Cited by 122 publications

(172 citation statements)

References 36 publications

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“…13,46 It has become clear that different types of stress signals as inputs result in different genes being transcribed under p53 control. 47 In addition stress signals received by different cell or tissue types also produce different transcriptional programs regulated by the p53 protein. We do not understand what mediates these different regulatory responses.…”

Section: The Downstream Events In the P53 Pathwaymentioning

confidence: 99%

The P53 pathway: what questions remain to be explored?

2006

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The p53 pathway is composed of hundreds of genes and their products that respond to a wide variety of stress signals. These responses to stress include apoptosis, cellular senescence or cell cycle arrest. In addition the p53-regulated genes produce proteins that communicate these stress signals to adjacent cells, prevent and repair damaged DNA and create feedback loops that enhance or attenuate p53 activity and communicate with other signal transduction pathways. Many questions remain to be explored in our understanding of how this network of genes plays a role in protection from cancers, therapy and integrating the homeostatic mechanisms of stress management and fidelity in a cell and organism. The goal of this chapter is to elucidate some of those questions and suggest new directions for this area of research.

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Section: The Downstream Events In the P53 Pathwaymentioning

confidence: 99%

The P53 pathway: what questions remain to be explored?

2006

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“…TP53 is a complex and multifunctional transcription factor known to respond to a broad variety of cellular stresses, including DNA damage, mitotic spindle damage, heat shock, metabolic changes, hypoxia, viral infection, and oncogene activation [70]. Our analyses found several interesting genes in the TP53 network: the Far upstream element-binding protein (FUBP1), known to regulate MYC proto-oncogene expression, the cytokine family with sequence similarity 3 member C (FAM3C), numerous proteolytic and metabolic genes (LIPA; CTSZ; P4HA1 and SF3B1), RANBP2 a small GTP-binding protein of the RAS superfamily and RAD54B a member of the SNF2/SWI2 superfamily that is involved in the recombinational repair of DNA damage.…”

Section: Low-dose Functions and Network Associated With Membranes Omentioning

confidence: 99%

Low dose radiation response curves, networks and pathways in human lymphoblastoid cells exposed from 1 to 10cGy of acute gamma radiation

Wyrobek

Manohar

Krishnan

et al. 2011

Mutation Research/Genetic Toxicology and Environmental Mutagene

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We investigated the low dose dependency of the transcriptional response of human cells to characterize the shape and biological functions associated with the dose response curve and to identify common and conserved functions of low dose expressed genes across cells and tissues.Human lymphoblastoid (HL) cells from two unrelated individuals were exposed to graded doses of radiation spanning the range of 1-10 cGy were analyzed by transcriptome profiling, qPCR and bioinformatics, in comparison to sham irradiated samples. A set of ~80 genes showed consistent responses in both cell lines; these genes were associated with homeostasis mechanisms (e.g., membrane signaling, molecule transport), subcellular locations (e.g., Golgi, and endoplasmic reticulum), and involved diverse signal transduction pathways. The majority of radiation-modulated genes had plateau-like responses across 1-10 cGy, some with suggestive evidence that transcription was modulated at doses below 1 cGy. MYC, FOS and TP53 were the major network nodes of the low-dose response in HL cells. Comparison our low dose expression findings in HL cells with those of prior studies in mouse brain after whole body exposure, in human keratinocyte cultures, and in endothelial cells cultures, indicates that certain components of the low dose radiation response are broadly conserved across cell types and tissues, independent of proliferation status.

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“…Furthermore, siRNA against p53 enhanced FAT10 promoter activity in the p53 þ / þ KB3-1 and 293 cell lines (Figure 4b) as well as FAT10 transcript expression in 293 cell line (Figure 4c). Downstream target genes that are negatively regulated by p53 include genes regulating apoptosis (Hoffman et al, 2002) and the G2/M of the cell cycle (Innocente et al, 1999;Zhao et al, 2000;Chun and Jin, 2003). One of the G2/M genes that are downregulated by p53 is MAD1 (Chun and Jin, 2003).…”

Section: Fat10 Is Negatively Regulated By P53mentioning

confidence: 99%

“…survivin) (Hoffman et al, 2002) and the G2/M phase of cell cycle (e.g. cyclin B1, cdc2, cdc25c, Mad1) (Innocente et al, 1999;Zhao et al, 2000;Chun and Jin, 2003). The mechanism of repression of genes by p53 is less clear.…”

Section: Introductionmentioning

confidence: 99%

p53 negatively regulates the expression of FAT10, a gene upregulated in various cancers

2006

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FAT10 is a member of the ubiquitin-like modifier family of proteins and has been implicated to play important roles in antigen presentation, cytokine response, apoptosis and mitosis. We have recently demonstrated the upregulation of FAT10 gene expression in 90% of hepatocellular carcinoma patients. Here, we identified and characterized the promoter of the FAT10 gene to elucidate the mechanism of FAT10 gene expression. Notably, we found that the 5 0 untranslated region (5 0 UTR), from the transcription start site to 15 bases before the translational start site, displays significant promoter activity. Regions upstream of the 5 0 UTR (from þ 26 to À1997) do not confer any promoter activity. Curiously, FAT10 promoter activity and expression is significantly repressed in KB3-1 and HepG2 cells, which have wild-type p53, than in p53-negative Hep3B cells. The role of p53 in regulating FAT10 expression was evident by the significant downregulation (Po0.05) of FAT10 mRNA expression and promoter activity when wild-type p53 was transfected into p53-null Hep3B cells. Conversely, inhibiting p53 expression through siRNA against p53 significantly enhanced FAT10 expression and promoter activity. p53 was found to bind in vivo to the 5 0 half consensus sequence of p53-binding site located at the FAT10 promoter. Hence, we propose that FAT10 is a downstream target of p53 and dysregulation of FAT10 expression in p53-defective cells could contribute to carcinogenesis.

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The Transcriptional Program following p53 Activation

Cited by 122 publications

References 36 publications

The P53 pathway: what questions remain to be explored?

The P53 pathway: what questions remain to be explored?

Low dose radiation response curves, networks and pathways in human lymphoblastoid cells exposed from 1 to 10cGy of acute gamma radiation

p53 negatively regulates the expression of FAT10, a gene upregulated in various cancers

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