Induction of hTERT expression and phosphorylation by estrogen via Akt cascade in human ovarian cancer cell lines

Kimura, Akiko; Ohmichi, Masahide; Koyama, Jun; Kyo, Satoru; Mabuchi, Seiji; Takahashi, Toshifumi; Ohshima, Chika; Arimoto-Ishida, Emi; Nishio, Yukihiro; Inoue, Masakí; Kurachi, Hirohisa; Tasaka, Keiichi; Murata, Yuji

doi:10.1038/sj.onc.1207582

Cited by 114 publications

(90 citation statements)

References 57 publications

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“…telomerase activity. It is shown that specific growth hormonereleasing hormone (GHRH) antagonists decrease telomerase activity in a glioblastoma cell line (34). It is of interest to note that the GHRH antagonist-mediated decrease in telomerase activity is also associated with down-regulation of hTERT mRNA and without change in the level of hTR or TP1 mRNA as is observed with autocrine hGH in this study.…”

Section: Discussionmentioning

confidence: 58%

αCP1 Mediates Stabilization of hTERT mRNA by Autocrine Human Growth Hormone

Emerald

Chen

Zhu

et al. 2007

Journal of Biological Chemistry

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We herein demonstrate that autocrine human growth hormone production in human mammary carcinoma cells results in increased telomerase activity as a result of specific up-regulation of telomerase catalytic subunit (human telomerase reverse transcriptase (hTERT)) mRNA and protein. This increase in hTERT gene expression is not due to increased transcriptional activation of the hTERT promoter but is the result of increased stability of hTERT mRNA exerted by CU-rich cis-regulatory sequences present in the 3-untranslated region of TERT mRNA. Autocrine human growth hormone up-regulates two poly(C)-binding proteins, ␣CP1 and ␣CP2, which bind to these cis-regulatory elements and stabilize hTERT mRNA. We have therefore demonstrated that post-transcriptional modulation of the level of hTERT mRNA is one mechanism for regulation of cellular telomerase activity.Chromosomal ends consist of small DNA repeats that are not duplicated faithfully during replication resulting in loss of DNA during each replication. To faithfully replicate chromosomal ends, cells use a reverse transcriptase holoenzyme termed the telomerase complex (1). The template human telomerase RNA (hTR) 3 and the reverse transcriptase catalytic subunit (hTERT) are considered to be the major components of the human telomerase complex, because the expression of hTERT and hTR alone is able to restore the majority of telomerase activity (2). Telomerase activity is subject to stringent regulation and is regulated by multiple mechanisms such as hTERT mRNA transcription (3), splicing and maturation (4), protein phosphorylation and transport (5), and subcellular localization of each component of the telomerase complex (6). Telomerase activity is minimal in most somatic cells resulting in chromosome shortening after each proliferative cycle eventually resulting in crisis and cell death (7). However, telomerase activity is readily detected in 90% of all tumor cells (8), in all tissues during early development (9), and in tissues with continuous proliferation, such as the hematopoietic system or the epidermis (10, 11).mRNA turnover is one important mechanism by which gene expression is regulated (13). Specific interactions between sequences within the mRNA (cis-acting regulatory elements) and cellular RNA-binding proteins (trans-acting factors) regulate ribonuclease action and subsequent mRNA decay rates. The majority of these cis-acting elements are present in the 3Ј-untranslated region (3Ј-UTR) of the mRNA. cis-Regulatory elements such as AU-rich elements (12), Iron-responsive element (14), and CU-rich elements (15) within the 3Ј-UTR have been demonstrated to possess a role in mRNA stability. ␣-Globin mRNA poly(C)-rich segment-binding proteins (␣CPs), also referred to as poly(C)-binding proteins, and hnRNP K bind to CU-rich cis-regulatory elements (16). Two of the five members of poly(C)-binding proteins, ␣CP1 and ␣CP2, are highly homologous (16). Both ␣CP1 and ␣CP2 bind to pyrimidinerich elements in the 3Ј-UTR and stabilize a variety of mRNAs including ␣-globin and eryt...

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Section: Discussionmentioning

confidence: 58%

αCP1 Mediates Stabilization of hTERT mRNA by Autocrine Human Growth Hormone

Emerald

Chen

Zhu

et al. 2007

Journal of Biological Chemistry

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“…At post-translational levels, we and others have shown that hTERT is a phosphoprotein and that phosphorylation by protein kinase C and Akt up-regulates telomerase activity [61][62][63]. Conversely, protein phosphatase 2A dephosphorylates hTERT and inhibits telomerase activity [61].…”

Section: Molecular Mechanisms Regulating Telomerase Activitymentioning

confidence: 92%

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

et al. 2006

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Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China and Southeast Asia. The disease is a poorly differentiated carcinoma without effective cure, and the mechanism underlying its development remains largely unknown. Of several factors identified in NPC aetiology in recent years, Epstein-Barr virus (EBV) infection has emerged to be most important. In almost all NPC cells, EBV uses several intracellular mechanisms to cause oncogenic evolution of the infected cells. One such mechanism by which EBV infection induces cellular immortalization is believed to be through the activation of telomerase, an enzyme that is normally repressed but becomes activated during cancer development. Studies show that greater than 85% of primary NPC display high telomerase activity by mechanisms involving EBV infection, consistent with the notion that EBV is commonly involved in inducing cell immortalization. More recently, different EBV proteins have been shown to activate or inhibit the human telomerase reverse transcriptase gene, by modulating intracellular signalling pathways. These findings suggest a new model with a number of challenges towards our understanding, molecular targeting and therapeutic intervention in NPC.

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“…Data from studies on hTERT derived peptides and on ovarian cancer cell lines have suggested that PKB/Akt induced phosphorylation of hTERT can upregulate telomerase activity. 25,36 The DJ-1 related regulation of PKB/Akt phosphorylation status can thus have dual consequences for hTERT, at the transcriptional and posttranscriptional level, with additive effects regarding telomerase activity. The siRNA experiments also verified that DJ-1 can influence the telomerase activity level.…”

Section: Discussionmentioning

confidence: 99%

“…22,23 PKB/Akt can also affect telomerase expression through post-transcriptional phosphorylation of the hTERT protein as indicated in studies on myeloma and ovarian cancer cells. 24,25 Thus, the PI-3-kinase-PKB/Akt pathway can interact with hTERT and telomerase expression at both the transcriptional and posttranscriptional level and since DJ-1 might be a potentially important regulator of this pathway the present study was undertaken to further investigate this issue in RCC. We demonstrate here an association among DJ-1, cMyc and hTERT gene expression levels in a large series of ccRCC indicating a putative signaling pathway in this tumor type.…”

mentioning

confidence: 99%

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

Sitaram

Cairney

Grabowski

et al. 2009

Intl Journal of Cancer

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DJ-1 is as a novel regulator of the tumor suppressor PTEN with stimulatory effects on PI3K-AKT/PKB signaling, one possible target of which is cMyc. The catalytic unit of the telomerase complex, hTERT, can be activated at different levels, including transcriptionally by cMyc and through phosphorylation by AKT/PKB. The aim of the study was to analyze the putative signaling pathway encompassing DJ-1, cMyc and hTERT in a series of 176 renal cell carcinomas (RCC) and experimentally in cell lines. DJ-1 mRNA expression was significantly elevated in clear cell RCC (ccRCC) compared with in papillary RCC (pRCC; p 5 0.005) and kidney cortex tissue (p < 0.001). ccRCC and pRCC demonstrated higher cMyc RNA levels than in kidney cortex (p < 0.001 for both) as well as increased levels of hTERT RNA (p < 0.001 and p 5 0.011, respectively). DJ-1 was positively correlated to cMyc and hTERT in ccRCC (p < 0.001 and p 5 0.019, respectively), but not in pRCC, indicating that this pathway could have a functional significance in ccRCC. siRNA knock down of DJ-1 induced downregulation of cMyc and hTERT mRNA associated with decreased expression of pAKT and cMyc protein levels. hTERT promoter activity was upregulated after DJ-1 transfection and this upregulation was inhibited after mutation of the cMyc binding sites. These experimental data support the functional link among DJ-1, cMyc and hTERT expression as indicated in the tumor material. Neither DJ-1, cMyc nor hTERT mRNA levels were associated with proliferation (S-phase fraction), telomere length or prognosis in ccRCC. ' UICCKey words: renal cell carcinoma; DJ-1; cMyc; hTERT; telomere length; proliferation; prognosis Renal cell carcinoma (RCC) constitutes a heterogeneous group of tumors regarding cytogenetic aberrations, morphologic appearance and clinical outcome. The WHO classification identifies different morphologic subtypes of sporadic RCC including the three most common types, clear cell (ccRCC), papillary (pRCC) and chromophobe RCC. 1 Each entity shows characteristic cytogenetic abnormalities indicating essential differences between the RCC subtypes regarding the mechanisms leading to tumor development.The phosphatase tensin homologue deleted on chromosome 10 (PTEN) protein is a well known tumor suppressor acting as a negative regulator of the phosphoinositide-3 (PI-3)-kinase pathway including the downstream Protein Kinase B (PKB)/Akt protein. In RCC, an association between decreased PTEN expression and high PKB/Akt activation has been described. 2 A novel protein, DJ-1 (also called Cap1/RS/PARK7), has been proposed to be involved in tumorigenesis by negatively regulating PTEN. 3 DJ-1 was first described as a protein showing a cooperative transforming activity with H-Ras in mouse NIH3T3 cells. 4 Overexpression of DJ-1 has been reported in several malignancies, including breast and lung. 5,6 Further, DJ-1 mRNA expression levels seemed to be associated with survival in lung cancer 3 and elevated levels of circulating DJ-1 and anti-DJ-1 auto-antibodies were detected in breast cance...

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Induction of hTERT expression and phosphorylation by estrogen via Akt cascade in human ovarian cancer cell lines

Cited by 114 publications

References 57 publications

αCP1 Mediates Stabilization of hTERT mRNA by Autocrine Human Growth Hormone

αCP1 Mediates Stabilization of hTERT mRNA by Autocrine Human Growth Hormone

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

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