Modulation of expression of RA-regulated genes by the oncoprotein v-erbA

Ventura-Holman, Tereza; Mamoon, Abulkhair; Subauste, José S.

doi:10.1016/j.gene.2008.08.006

Cited by 7 publications

(4 citation statements)

References 25 publications

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“…Notably the mutant TRs isolated from human HCCs function not only as dominant-negative inhibitors on certain reporter genes but often have sustained additional mutations that alter their DNA recognition properties (Chan and Privalsky, 2006). A similar phenomenon was observed for the oncogenic v-Erb A allele and for certain RCCC-TR mutants (Bonde and Privalsky, 1990; Chen et al , 1993; Sharif and Privalsky, 1991; Ventura-Holman et al , 2008; Rosen and Privalsky, 2009). We hypothesized that these changes might confer an altered target gene repertoire that contributes to the ability of these receptors to induce neoplasia.…”

Section: Discussionsupporting

confidence: 71%

Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene repertoire

Chan

Privalsky

2009

Oncogene

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Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that control multiple aspects of normal physiology and development. Mutations in TRs have been identified at high frequency in certain cancers, including human hepatocellular carcinomas (HCCs). The majority of HCC TR mutants bear lesions within their DNA recognition domains, and we have hypothesized that these lesions change the mutant receptors' target gene repertoire in a way crucial to their function as oncoproteins. Using stable cell transformants and expression array analysis, we determined that mutant TRs isolated from two different HCCs do, as hypothesized, display a target gene repertoire distinct from that of their normal TR progenitors. Only a subset of genes regulated by wild-type TRs were regulated by the corresponding HCC-TR mutants. More surprisingly, the HCC-TR mutants also gained the ability to regulate additional target genes not recognized by the wild-type receptors, and were not simply restricted to repression, but could also activate a subset of their target genes. We conclude that the TR mutants isolated from HCC have sustained multiple alterations from their normal progenitors that include not only changes in their transcriptional outputs, but also changes in the genes they target; both are likely to contribute to neoplasia.

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Section: Discussionsupporting

confidence: 71%

Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene repertoire

Chan

Privalsky

2009

Oncogene

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“…They also reported that genes that promote apoptosis are inhibited and, conversely, genes that inhibit apoptosis are induced (Mamoon et al, 2008). Furthermore they expanded their work by investigating the effect of v‐erbA, an oncogene known to exert dominant—negative effect on the expression of retinoic acid responsive genes in order to understand nuclear receptor mediated transcriptional regulation in murine hepatocytes in culture (Ventura‐Holman et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Retinoid‐responsive transcriptional changes in epidermal keratinocytes

Lee

Stojadinović

Krzyzanowska

et al. 2009

Journal Cellular Physiology

103

101

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Retinoids (RA) have been used as therapeutic agents for numerous skin diseases, from psoriasis to acne and wrinkles. While RA is known to inhibit keratinocyte differentiation, the molecular effects of RA in epidermis have not been comprehensively defined. To identify the transcriptional targets of RA in primary human epidermal keratinocytes, we compared the transcriptional profiles of cells grown in the presence or absence of all-trans retinoic acid for 1, 4, 24, 48 and 72 hours, using large DNA microarrays. As expected, RA suppresses the protein markers of cornification; however the genes responsible for biosynthesis of epidermal lipids, long-chain fatty acids, cholesterol, and sphingolipids, are also suppressed. Importantly, the pathways of RA synthesis, esterification and metabolism are activated by RA; therefore, RA regulates its own bioavailability. Unexpectedly, RA regulates many genes associated with the cell cycle and programmed cell death. This led us to reveal novel effects of RA on keratinocyte proliferation and apoptosis. The response to RA is very fast: 315 genes were regulated already after 1 h. More than one-third of RA-regulated genes function in signal transduction and regulation of transcription. Using in silico analysis, we identified a set of over-represented transcription factor binding sites in the RA-regulated genes. Many psoriasis-related genes are regulated by RA, some induced, others suppressed. These results comprehensively document the transcriptional changes caused by RA in keratinocytes, add new insights into the molecular mechanism influenced by RA in the epidermis and demonstrate the hypothesis-generating power of DNA microarray analysis.

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“…Additional methods such in vivo models of liver disease, flow cytometry, Percoll-based purification, immunofluorescence, siRNA-mediated knockdown of Klf6 and MafF and LUMINEX assays, together with a complete list of chemicals, reagents, antibodies and tables containing gene expression data and bioinformatics, are provided in the supplemental section. Additional gene expression data (based on Affymetrix gene arrays) including mouse HCC (Dapito et al 2012 ), mouse cell lines AML12 (Ventura-Holman et al 2008 ) and iHep (stem cell-derived hepatocytes) (Morris et al 2014 ), human cell lines HepG2 (Rodrigues et al 2016 ) and HLC (stem cell-derived hepatocytes) (Godoy et al 2015 ), human hepatitis B-infected liver (Farci et al 2010 ), human non-alcoholic fatty liver (NAFLD) (Moylan et al 2014 ), human cirrhosis and hepatocellular carcinoma (HCC) (Yildiz et al 2013 ) were obtained from Gene Expression Omnibus http://www.ncbi.nlm.nih.gov/geo/ or ArrayExpress https://www.ebi.ac.uk/arrayexpress/ and provided in the supplemental section.…”

Section: Methodsmentioning

confidence: 99%

Gene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue

et al. 2016

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It is well known that isolation and cultivation of primary hepatocytes cause major gene expression alterations. In the present genome-wide, time-resolved study of cultivated human and mouse hepatocytes, we made the observation that expression changes in culture strongly resemble alterations in liver diseases. Hepatocytes of both species were cultivated in collagen sandwich and in monolayer conditions. Genome-wide data were also obtained from human NAFLD, cirrhosis, HCC and hepatitis B virus-infected tissue as well as mouse livers after partial hepatectomy, CCl4 intoxication, obesity, HCC and LPS. A strong similarity between cultivation and disease-induced expression alterations was observed. For example, expression changes in hepatocytes induced by 1-day cultivation and 1-day CCl4 exposure in vivo correlated with R = 0.615 (p < 0.001). Interspecies comparison identified predominantly similar responses in human and mouse hepatocytes but also a set of genes that responded differently. Unsupervised clustering of altered genes identified three main clusters: (1) downregulated genes corresponding to mature liver functions, (2) upregulation of an inflammation/RNA processing cluster and (3) upregulated migration/cell cycle-associated genes. Gene regulatory network analysis highlights overrepresented and deregulated HNF4 and CAR (Cluster 1), Krüppel-like factors MafF and ELK1 (Cluster 2) as well as ETF (Cluster 3) among the interspecies conserved key regulators of expression changes. Interventions ameliorating but not abrogating cultivation-induced responses include removal of non-parenchymal cells, generation of the hepatocytes’ own matrix in spheroids, supplementation with bile salts and siRNA-mediated suppression of key transcription factors. In conclusion, this study shows that gene regulatory network alterations of cultivated hepatocytes resemble those of inflammatory liver diseases and should therefore be considered and exploited as disease models.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1761-4) contains supplementary material, which is available to authorized users.

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Modulation of expression of RA-regulated genes by the oncoprotein v-erbA

Cited by 7 publications

References 25 publications

Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene repertoire

Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene repertoire

Retinoid‐responsive transcriptional changes in epidermal keratinocytes

Gene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue

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