The Promoter of Human Telomerase Reverse Transcriptase Is Activated During Liver Regeneration and Hepatocyte Proliferation

Sirma, Hüseyin; Kumar, Mukesh; Meena, Jitendra K.; Witt, Britta; Weise, Julia M.; Lechel, André; Satyanarayana, A.; Sakk, Vadim; Guguen‐Guillouzo, Christiane; Zender, Lars; Rudolph, K. Lenhard; Güneş, Çagatay

doi:10.1053/j.gastro.2011.03.047

Cited by 34 publications

(46 citation statements)

References 38 publications

(49 reference statements)

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“…It is important to note that our data for TERT-mediated inhibition of liver proliferation in livers of old mice after CCl 4 treatment do not support previous observations obtained in studies of liver regeneration after partial hepatectomy (PH). It has been shown that TERT activity was increased after PH in pig's livers (31) and that hTERT promoter is activated during liver proliferation in mouse hepatocytes (32). However, our data with CCl 4 -mediated liver proliferation in livers of old mice showed that the reduction of TERT is involved in the increased liver proliferation.…”

Section: Discussioncontrasting

confidence: 69%

Age-associated Change of C/EBP Family Proteins Causes Severe Liver Injury and Acceleration of Liver Proliferation after CCl4 Treatments

Hong

Lewis

Iakova

et al. 2014

Journal of Biological Chemistry

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Background: Older patients are more sensitive to drug-mediated development of liver disorders. Results: Age and CCl 4 treatments change expression of C/EBP proteins leading to repression of key regulators of liver biology. Conclusion:The age-associated alterations of C/EBP proteins cause severe liver injury after CCl 4 treatments. Significance: Understanding of mechanisms of age-associated severe liver injury is important for development of therapeutic approaches.

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Section: Discussioncontrasting

confidence: 69%

Age-associated Change of C/EBP Family Proteins Causes Severe Liver Injury and Acceleration of Liver Proliferation after CCl4 Treatments

Hong

Lewis

Iakova

et al. 2014

Journal of Biological Chemistry

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“…In fact, while telomerase activity is usually undetectable in adult human tissues, several organs of normal adult rodents display substantial amounts of telomerase activity; in particular, in the liver telomerase is expressed at a nearly constant level throughout life and decreases during liver regeneration. 34,35 Indeed, we did not observe an increase of telomerase expression in any of the lesions we examined (data not shown). This remarkable difference between animal species may reflect the different regulation mechanisms of telomerase expression.…”

Section: Discussionmentioning

confidence: 65%

Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

et al. 2015

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Hepatocellular carcinoma (HCC) develops through a multistage process, but the nature of the molecular changes associated with the different steps, the very early ones in particular, is largely unknown. Recently, dysregulation of the NRF2/KEAP1 pathway and mutations of these genes have been observed in experimental and human tumors, suggesting their possible role in cancer development. To assess whether Nrf2/Keap1 mutations are early or late events in HCC development, we investigated their frequency in the rat Resistant Hepatocyte model, consisting of the administration of diethylnitrosamine followed by a brief exposure to 2-acetylaminofluorene. This model enables the dissection of all stages of hepatocarcinogenesis. We found that Nrf2/Keap1 mutations were present in 71% of early preneoplastic lesions and in 78.6% and 59.3% of early and advanced HCCs, respectively. Mutations of Nrf2 were more frequent, missense, and located in the Nrf2-Keap1 binding region. Mutations of Keap1 occurred at a much lower frequency in both preneoplastic lesions and HCCs and were mutually exclusive with those of Nrf2. Functional in vitro and in vivo studies showed that Nrf2 silencing inhibited the ability of tumorigenic rat cells to grow in soft agar and to form tumors. Unlike Nrf2 mutations, those of Ctnnb1, which are frequent in human HCC, were a later event as they appeared only in fully advanced HCCs (18.5%). Conclusion: In the Resistant Hepatocyte model of hepatocarcinogenesis the onset of Nrf2 mutations is a very early event, likely essential for the clonal expansion of preneoplastic hepatocytes to HCC, while Ctnnb1 mutations occur only at very late stages. Moreover, functional experiments demonstrate that Nrf2 is an oncogene critical for HCC progression and development. (HEPATOLOGY 2015;62:851-862) See Editorial on Page 677 H epatocellular carcinoma (HCC) is the third most frequent cause of cancer-related deaths worldwide. 1 Unfortunately, our knowledge of the genomic alterations implicated in HCC initiation and progression is still fragmentary. Moreover, different from other solid tumors, no driving genetic alteration to which tumor cells are addicted and that can be effectively targeted has ever been identified. In this scenario, HCC is probably one of the tumor types where a more complete understanding of the underlying genetic alterations could have a major impact on the development of new treatment strategies. Also known as NFE2L2, NRF2 is of particular interest as conflicting results have been reported concerning the role of the NRF2/KEAP1 pathway in cancer development. 2 It is a master transcriptional activator of genes encoding enzymes that protect cells from oxidative stress and

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“…After 10 days post PH, no significant rDNA could be precipitated with the telomerase antibody AB8313. Notably, endogenous telomerase activity is not significantly altered in regenerating liver 15 . Thus, rDNA occupancy of telomerase is a feature of proliferating hepatocytes.…”

Section: Resultsmentioning

confidence: 88%

“…Second, to analyse whether TERT binding to rDNA is restricted to transformed cells and to better understand telomerase activity at the rDNA locus in vivo, we performed partial hepatectomies (PH) on the mice. PH triggers up to 80% of the resting, telomerase-positive hepatocytes in mice to enter the cell cycle and actively replicate 15 . Mice were subjected to PH and killed at different time points, and rDNA transcription and the binding kinetics of telomerase to rDNA were monitored (Fig.…”

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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The Promoter of Human Telomerase Reverse Transcriptase Is Activated During Liver Regeneration and Hepatocyte Proliferation

Cited by 34 publications

References 38 publications

Age-associated Change of C/EBP Family Proteins Causes Severe Liver Injury and Acceleration of Liver Proliferation after CCl4 Treatments

Age-associated Change of C/EBP Family Proteins Causes Severe Liver Injury and Acceleration of Liver Proliferation after CCl4 Treatments

Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions

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