Disruption of Trp53 in Livers of Mice Induces Formation of Carcinomas With Bilineal Differentiation

Katz, Sarah–Fee; Lechel, André; Obenauf, Anna C.; Begus‐Nahrmann, Yvonne; Kraus, Johann M.; Hoffmann, Eva Maria; Duda, Johanna; Eshraghi, Parisa; Hartmann, Daniel; Liss, Birgit; Schirmacher, Peter; Kestler, Hans A.; Speicher, Michael R.; Rudolph, K. Lenhard

doi:10.1053/j.gastro.2012.02.009

Cited by 80 publications

(89 citation statements)

References 51 publications

(43 reference statements)

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“…This observation is consistent with previous reports showing TERC localization in the nucleoli of HeLa cells 7,17 . Moreover, when liver tumour cells derived from Terc À / À mice 18 were subjected to ChIP analysis, no binding of TERT to the rDNA promoter was detectable, arguing that the presence of TERC in the telomerase complex is necessary for the association of TERT with the rDNA (Fig. 3f).…”

Section: Resultsmentioning

confidence: 99%

Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions

et al. 2014

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In addition to performing its canonical function, Telomerase Reverse Transcriptase (TERT) has been shown to participate in cellular processes independent of telomerase activity. Furthermore, although TERT mainly localizes to Cajal bodies, it is also present within the nucleolus. Because the nucleolus is the site of rDNA transcription, we investigated the possible role of telomerase in regulating RNA polymerase I (Pol I). Here we show that TERT binds to rDNA and stimulates transcription by Pol I during liver regeneration and Ras-induced hyperproliferation. Moreover, the inhibition of telomerase activity by TERT-or TERC-specific RNA interference, the overexpression of dominant-negative-TERT, and the application of the telomerase inhibitor imetelstat reduce Pol I transcription and the growth of tumour cells. In vitro, telomerase can stimulate the formation of the transcription initiation complex. Our results demonstrate how non-canonical features of telomerase may direct Pol I transcription in oncogenic and regenerative hyperproliferation.

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Section: Resultsmentioning

confidence: 99%

Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions

et al. 2014

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“…The fact that Rb family mutant mice only developed hepatocytic tumors and not bile duct tumors suggests that in this context, too, loss of RB function may alter the fate of adult stem cells . In contrast, loss of the p53 tumor suppressor in liver stem cells results in the development of tumors with bilineal differentiation (Katz et al 2012).…”

Section: Liver Oval Cellsmentioning

confidence: 99%

The retinoblastoma tumor suppressor and stem cell biology

Sage¹

2012

Genes Dev.

107

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Stem cells play a critical role during embryonic development and in the maintenance of homeostasis in adult individuals. A better understanding of stem cell biology, including embryonic and adult stem cells, will allow the scientific community to better comprehend a number of pathologies and possibly design novel approaches to treat patients with a variety of diseases. The retinoblastoma tumor suppressor RB controls the proliferation, differentiation, and survival of cells, and accumulating evidence points to a central role for RB activity in the biology of stem and progenitor cells. In some contexts, loss of RB function in stem or progenitor cells is a key event in the initiation of cancer and determines the subtype of cancer arising from these pluripotent cells by altering their fate. In other cases, RB inactivation is often not sufficient to initiate cancer but may still lead to some stem cell expansion, raising the possibility that strategies aimed at transiently inactivating RB might provide a novel way to expand functional stem cell populations. Future experiments dedicated to better understanding how RB and the RB pathway control a stem cell's decisions to divide, self-renew, or give rise to differentiated progeny may eventually increase our capacity to control these decisions to enhance regeneration or help prevent cancer development. Basic functions of the RB pathwayThe human retinoblastoma gene RB1 was initially cloned from children with a rare form of eye cancer of the same name. Since this seminal discovery, RB has been found to be inactivated in a wide range of pediatric and adult human cancers. The mechanisms of tumor suppression by the RB protein are thought to largely involve its ability to restrict cell cycle progression at the G1/S transition of the cell cycle by inhibition of E2F transcription factors. Phosphorylation of RB by Cyclin/Cdk (cyclin-dependent kinase) complexes can inhibit the ability of RB to bind to E2F. Cyclin/Cdk complexes are themselves under the control of small cell cycle inhibitors of the INK4 and CIP/KIP families, to which p16Ink4a and p21 Cip1 , respectively, belong. The module comprising INK4-CIP/KIP cell cycle inhibitors; Cyclin/Cdk complexes; RB and its two family members, p107 and p130; and E2F transcription factors constitutes the RB pathway in cells.

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Section: Quiescencementioning

confidence: 99%

“…In mice, deletion of p53 increases the selfrenewal of HSCs, liver progenitor cells and neu ronal stem cells [65][66][67][68][69] and induces selfrenewal activity in progenitor cells that normally cannot selfrenew 70 . Moreover, p53 deletion also enhances the reprogram ming efficiency of differentiated cells into pluripotent cells 71 and the spontaneous dedifferentiation of differen tiated cells 68 . Enhanced dedifferentiation and increased selfrenewal of stem and progenitor cells in response to p53 deletion are associated with increased rates of cance r development 68,70,72 , suggesting that inhibition of both processes contributes to p53dependent cancer sup pression.…”

Section: Quiescencementioning

confidence: 99%

DNA damage checkpoints in stem cells, ageing and cancer

Sperka

Wang

Rudolph

2012

Nat Rev Mol Cell Biol

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359

300

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DNA damage induces cell-intrinsic checkpoints, including p53 and retinoblastoma (RB), as well as upstream regulators (exonuclease 1 (EXO1), ataxia telangiectasia mutated (ATM), ATR, p16(INK4a) and p19(ARF)) and downstream targets (p21, PUMA (p53 upregulated modulator of apoptosis) and sestrins). Clearance of damaged cells by cell-intrinsic checkpoints suppresses carcinogenesis but as a downside may impair stem cell and tissue maintenance during ageing. Modulating the activity of DNA damage checkpoints can either accelerate or decelerate tissue ageing and age-related carcinogenesis. The outcome depends on cell-intrinsic and cell-extrinsic mechanisms that regulate the clearance of damaged cells and on the molecular context in ageing tissues, including the level of DNA damage accumulation itself.

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Disruption of Trp53 in Livers of Mice Induces Formation of Carcinomas With Bilineal Differentiation

Cited by 80 publications

References 51 publications

Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions

Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions

The retinoblastoma tumor suppressor and stem cell biology

DNA damage checkpoints in stem cells, ageing and cancer

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