Liver-Specific pRB Loss Results in Ectopic Cell Cycle Entry and Aberrant Ploidy

Mayhew, Christopher N.; Bosco, Emily E.; Fox, Sejal R.; Okaya, Tomohisa; Tarapore, Pheruza; Schwemberger, Sandy; Babcock, George F.; Lentsch, Alex B.; Fukasawa, Kenji; Knudsen, Erik S.

doi:10.1158/0008-5472.can-04-4221

Cited by 98 publications

(110 citation statements)

References 65 publications

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“…In good agreement with the epidemiologic observations, mice with a liver-specific ablation of the Rb gene showed aberrant ploidy and increased multiplicity of liver tumors when exposed to DEN (Mayhew et al 2005;Mayhew et al 2007;Srinivasan et al 2007). To explore the role of AHR/RB/TGF-β interactions in liver tumorigenesis, we have examined the expression status of Tgfb genes, tumor suppressor genes, Ahr and several of its downstream targets in DEN-induced liver tumors and normal livers of mice with a liver-specific ablation of the Rb gene and in their wild-type littermates.…”

Section: Introductionsupporting

confidence: 85%

“…Genotypes were determined by standard PCR of tail DNA and deletion or retention of the Rb gene was confirmed by genotyping the mouse livers themselves. Characterization of these tumors has been reported elsewhere (Mayhew et al 2005;Mayhew et al 2007;Srinivasan et al 2007). …”

Section: Micementioning

confidence: 93%

“…These mice were then interbred with Rb fl/fl mice to produce Rb fl/fl (wild type) and Rb fl/fl AlbCre +/0 (RB-knockout) littermates at a 1:1 ratio (Mayhew et al, 2005). Mice were housed in a pathogen-free animal facility under standard 12-hour light/12-hour dark cycle with ad libitum water and chow.…”

Section: Micementioning

confidence: 99%

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Repression of Ah receptor and induction of transforming growth factor-β genes in DEN-induced mouse liver tumors

Mayhew

Schnekenburger

et al. 2008

Toxicology

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the biologic and toxic effects of its xenobiotic ligands. In recent years it has become evident that in the absence of ligand the AHR promotes cell cycle progression and that its activation by high-affinity ligands results in interactions with the retinoblastoma protein (RB) that lead to perturbation of the cell cycle, G 0 /G 1 arrest, diminished capacity for DNA replication and inhibition of cell proliferation. Hence, the AHR has diametrically opposed pro-proliferative and anti-proliferative functions that have yet to be reconciled at the molecular level. Work from our own and from other laboratories suggests that the AHR may function as a tumor suppressor gene that becomes silenced in the process of tumor formation. To develop preliminary support for a more thorough examination of this hypothesis we characterized the expression levels of various tumor suppressor genes, transforming growth factor-β (Tgfb) genes and the Ahr gene in liver tumor samples from mice with a liver-specific RB ablation and their wild-type littermates. In tumors arising in RB-positive livers, Cdkn2d and Tgfb1 were repressed and Cdkn2c, Tgfb2, Tgfb3 and Pai1 were induced, whereas in RB-negative tumors, only Cdkn2c and Tgfb3 were induced. Ahr was significantly repressed in tumors from both sets of mice, supporting the concept that Ahr silencing may be associated with cancer progression.

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Section: Introductionsupporting

confidence: 85%

Section: Micementioning

confidence: 93%

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Repression of Ah receptor and induction of transforming growth factor-β genes in DEN-induced mouse liver tumors

Mayhew

Schnekenburger

et al. 2008

Toxicology

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“…Duplicate samples of saponin-permeabilized isolated adipocytes were stained with PI and analyzed by flow cytometry for GFP and DNA content to assess the nuclear ploidy as an indicator of cell fusion events (19). Flow cytometric analysis with singlet discrimination demonstrated that 0.5%-1.5% of the GFP + adipocyte population displayed multinuclear content characteristic of increased nuclear ploidy or putative cell fusion events (Figure 4).…”

Section: Figurementioning

confidence: 99%

Rosiglitazone promotes development of a novel adipocyte population from bone marrow–derived circulating progenitor cells

Crossno¹,

Majka²,

Grazia³

et al. 2006

J. Clin. Invest.

238

205

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Obesity and weight gain are characterized by increased adipose tissue mass due to an increase in the size of individual adipocytes and the generation of new adipocytes. New adipocytes are believed to arise from resident adipose tissue preadipocytes and mesenchymal progenitor cells. However, it is possible that progenitor cells from other tissues, in particular BM, could also contribute to development of new adipocytes in adipose tissue. We tested this hypothesis by transplanting whole BM cells from GFP-expressing transgenic mice into wild-type C57BL/6 mice and subjecting them to a high-fat diet or treatment with the thiazolidinedione (TZD) rosiglitazone (ROSI) for several weeks. Histological examination of adipose tissue or FACS of adipocytes revealed the presence of GFP + multilocular (ML) adipocytes, whose number was significantly increased by ROSI treatment or high-fat feeding. These ML adipocytes expressed adiponectin, perilipin, fatty acid-binding protein (FABP), leptin, C/EBPα, and PPARγ but not uncoupling protein-1 (UCP-1), the CD45 hematopoietic lineage marker, or the CDllb monocyte marker. They also exhibited increased mitochondrial content. Appearance of GFP + ML adipocytes was contemporaneous with an increase in circulating levels of mesenchymal and hematopoietic progenitor cells in ROSI-treated animals. We conclude that TZDs and high-fat feeding promote the trafficking of BM-derived circulating progenitor cells to adipose tissue and their differentiation into ML adipocytes.

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“…RB has also been shown to have a crucial role in the maintenance of the quiescent state (Sage et al, 2003). Acute inactivation of RB in adult liver using conditional targeting shows that RB loss alone results in the deregulation of E2F regulatory genes, and induces senescent or quiescent hepatocytes to re-enter cell cycle progression (Mayhew et al, 2005). In addition to G1/S regulation, recent analysis using a microarray shed light on G2-M regulation by the RB/E2F pathway.…”

Section: Introductionmentioning

confidence: 99%

RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene

et al. 2006

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As alterations in retinoblastoma (RB)/E2F pathway are commonly found in human cancers, the molecular mechanism underlying cell cycle deregulation caused by the mutations in the RB/E2F pathway needs to be investigated extensively. Compared with good understanding of RB/E2F functions in G1-S cell cycle progression, it is not fully understood how an abrogated RB pathway affects the G2-M phase of the cell cycle. Here, we report that disruption of RB accelerated G2-M progression in the presence of DNA damage by elevating the expression of a set of mitotic regulatory genes. We generated RB( þ )-and (À)-matched cells using short hairpin RNA. In the RB(À) cells, the G2/M checkpoint mediated by a DNA-damaging agent was over-ridden. With microarray analysis, we found that the expression of key G2-M regulatory genes was upregulated in RB(À) cells. In particular, we demonstrated that the proto-oncogene ECT2 was directly regulated by E2Fs. Furthermore, suppression of ECT2 expression by small interfering RNA in RB(À) cells resulted in cytokinesis arrest, suggesting that RB(À) cells lack the regulation of E2F-mediated cytokinesis. These results indicate that aberrant ECT2 expression, observed in various human tumors, could be the direct result of RB/E2F pathway deficiency, thereby contributing to cell division in cancers.

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Liver-Specific pRB Loss Results in Ectopic Cell Cycle Entry and Aberrant Ploidy

Cited by 98 publications

References 65 publications

Repression of Ah receptor and induction of transforming growth factor-β genes in DEN-induced mouse liver tumors

Repression of Ah receptor and induction of transforming growth factor-β genes in DEN-induced mouse liver tumors

Rosiglitazone promotes development of a novel adipocyte population from bone marrow–derived circulating progenitor cells

RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene

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