Involvement of 14-3-3 proteins in nuclear localization of telomerase

Seimiya, Hiroyuki; Sawada, Hiroko; Muramatsu, Yukiko; Shimizu, Mayuko; Ohko, Kumiko; Yamane, Kunio; Tsuruo, Takashi

doi:10.1093/emboj/19.11.2652

Cited by 276 publications

(246 citation statements)

References 61 publications

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“…Regulation of subcellular localization of the binding partner is one of the main 'modes of function' of the 14-3-3 proteins (Muslin and Xing, 2000;Tzivion et al, 2001). Examples of this mode of regulation include protein phosphatase Cdc25C (Dalal et al, 1999), histone deacetylase (Grozinger and Schreiber, 2000), telomerase (Seimiya et al, 2000) and protein kinase U-a (Zhang et al, 1999). In agreement with this hypothesis, the 14-3-3 protein has been shown to physically interact with both parts of bipartite NLS of phosphorylated FOXO4 (fragment 11-213) (Obsilova et al, 2005).…”

Section: Phosphorylation Of the Foxo Dbdmentioning

confidence: 99%

Structure/function relationships underlying regulation of FOXO transcription factors

2008

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The FOXO subgroup of forkhead transcription factors plays a central role in cell-cycle control, differentiation, metabolism control, stress response and apoptosis. Therefore, the function of these important molecules is tightly controlled by a wide range of protein-protein interactions and posttranslational modifications including phosphorylation, acetylation and ubiquitination. The mechanisms by which these processes regulate FOXO activity are mostly elusive. This review focuses on recent advances in structural studies of forkhead transcription factors and the insights they provide into the mechanism of DNA recognition. On the basis of these data, we discuss structural aspects of protein-protein interactions and posttranslational modifications that target the forkhead domain and the nuclear localization signal of FOXO proteins.

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Section: Phosphorylation Of the Foxo Dbdmentioning

confidence: 99%

Structure/function relationships underlying regulation of FOXO transcription factors

2008

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“…The hTERT-HA expression vector has been described (Seimiya et al 2000). The HAubiquitin expression vector was constructed by cloning the BamHI and XbaI fragment encoding the ubiqutin cDNA into pcDNA3.1 (Invitrogen) (J.S.…”

Section: Expression Vectorsmentioning

confidence: 99%

Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT

Kim¹,

Park²,

Kang³

et al. 2005

Genes Dev.

162

158

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Telomere homeostasis is regulated by telomerase and a collection of associated proteins. Telomerase is, in turn, regulated by post-translational modifications of the ratelimiting catalytic subunit hTERT. Here we show that disruption of Hsp90 by geldanamycin promotes efficient ubiquitination and proteasome-mediated degradation of hTERT. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length. Our data suggest that MKRN1 plays an important role in modulating telomere length homeostasis through a dynamic balance involving hTERT protein stability.

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“…One possible mechanism for the post-translational modifications of telomerase is the interaction of hTERT with accessory proteins. Recently, it was reported that 14-3-3 proteins, which have been proposed to be important in controlling intracellular signaling cascades by associating with a number of different signaling proteins (Moorhead et al, 1996) and to work as molecular chaperones or to regulate intracellular localization of their binding partners (Yang et al, 1999), are post-translational modifiers of telomerase that function by controlling the intracellular localization of hTERT (Seimiya et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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We examined the mechanism by which estrogen regulates telomerase activity in Caov-3 human ovarian cancer cell lines, which express ER, to determine whether the regulation affects the expression and/or phosphorylation of the telomerase catalytic subunit (hTERT). 17b-Estradiol (E 2 ) induced telomerase activity and hTERT expression. Transient expression assays using luciferase reporter plasmids containing various fragments of hTERT promoter showed that the estrogen-responsive element appeared to be partially responsible for the E 2 -induced activation of the hTERT promoter. Either pretreatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, or transfection with a dominantnegative Akt attenuated the E 2 -induced activation of the hTERT promoter. In addition, estrogen induced the phosphorylation of IjB inhibitor protein via the Akt cascade, and cotransfection with a dominant-negative subunit of NFjB attenuated the response of the ERE-deleted hTERT promoter to E 2 . Moreover, E 2 induced the phosphorylation of hTERT, the association of 14-3-3 protein and NFjB with hTERT, and nuclear accumulation of hTERT in an Akt-dependent manner. These results indicate that E 2 induces telomerase activity not only by transcriptional regulation of hTERT via an ERE-dependent mechanism and a PI3K/Akt/NFjB cascade, but also by post-transcriptional regulation via Akt-dependent phosphorylation of hTERT. Thus, the phosphorylation of Akt is a key event in the induction of telomerase activity by E 2 in human ovarian cancer cells.

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Involvement of 14-3-3 proteins in nuclear localization of telomerase

Cited by 276 publications

References 61 publications

Structure/function relationships underlying regulation of FOXO transcription factors

Structure/function relationships underlying regulation of FOXO transcription factors

Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT

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

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