Translation of the radioresistance kinase TLK1B is induced by γ-irradiation through activation of mTOR and phosphorylation of 4E-BP1

Sunavala‐Dossabhoy, Gulshan; Fowler, Marcie; Benedetti, Arrigo De

doi:10.1186/1471-2199-5-1

Cited by 54 publications

(26 citation statements)

References 21 publications

(25 reference statements)

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“…3E). Akt has been shown to activate mTOR, which plays an important role in protein synthesis (33). We next examined a role of mTOR in CO-induced phosphorylation of p70 S6K and eIF-4E.…”

Section: Co-induced Increases In Hif-1␣ and Vegf Expression Arementioning

confidence: 99%

Carbon Monoxide Promotes VEGF Expression by Increasing HIF-1α Protein Level via Two Distinct Mechanisms, Translational Activation and Stabilization of HIF-1α Protein

Choi

Kim

Lee

et al. 2010

Journal of Biological Chemistry

138

132

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Carbon monoxide (CO) plays a significant role in vascular functions. We here examined the molecular mechanism by which CO regulates HIF-1 (hypoxia-inducible transcription factor-1)-dependent expression of vascular endothelial growth factor (VEGF), which is an important angiogenic factor. We found that astrocytes stimulated with CORM-2 (CO-releasing molecule) promoted angiogenesis by increasing VEGF expression and secretion. CORM-2 also induced HO-1 (hemeoxygenase-1) expression and increased nuclear HIF-1␣ protein level, without altering its promoter activity and mRNA level. VEGF expression was inhibited by treatment with HIF-1␣ siRNA and a hemeoxygenase inhibitor, indicating that CO stimulates VEGF expression via up-regulation of HIF-1␣ protein level, which is partially associated with HO-1 induction. CORM-2 activated the translational regulatory proteins p70S6k and eIF-4E as well as phosphorylating their upstream signal mediators Akt and ERK. These translational signal events and HIF-1␣ protein level were suppressed by inhibitors of phosphatidylinositol 3-kinase (PI3K), MEK, and mTOR, suggesting that the PI3K/Akt/mTOR and MEK/ERK pathways are involved in a translational increase in HIF-1␣. In addition, CORM-2 also increased stability of the HIF-1␣ protein by suppressing its ubiquitination, without altering the proline hydroxylase-dependent HIF-1␣ degradation pathway. CORM-2 increased HIF-1␣/HSP90␣ interaction, which is responsible for HIF-1␣ stabilization, and HSP90-specific inhibitors decreased this interaction, HIF-1␣ protein level, and VEGF expression. Furthermore, HSP90␣ knockdown suppressed CORM-2-induced increases in HIF-1␣ and VEGF protein levels. These results suggest that CO stimulates VEGF production by increasing HIF-1␣ protein level via two distinct mechanisms, translational stimulation and protein stabilization of HIF-1␣.Carbon monoxide (CO) is a diffusible gas that has recently been found to play an important role in several biological processes, including angiogenesis and cytoprotection (1-4). CO is the product of the breakdown of heme by heme oxygenase (HO) 2 enzymes (5). There are two heme oxygenase functional isoforms: an inducible form, HO-1, and a constitutive form, HO-2. CO produced from heme by the catalytic reaction of HO induces the synthesis of angiogenic mediators, such as vascular endothelial growth factor (VEGF), IL-8, and stromal cell-derived factor-1, as well as decreasing the anti-angiogenic factors, namely soluble VEGF receptor-1 and soluble endoglin, resulting in the promotion of endothelial cell proliferation, migration, and anti-apoptotic responses (6 -9). In addition, glutamate-induced CO in astrocytes can act as a signal or regulatory molecule that contributes to the homeostatic regulation of vascular functions such as vasodilation (10, 11).HIF-1 (hypoxia-inducible factor) is a transcriptional complex involved in the regulation of crucial aspects of cellular functions, such as cell proliferation, survival, invasion, and glucose metabolism (12, 13). HIF-1 is composed of two s...

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“…3E). Akt has been shown to activate mTOR, which plays an important role in protein synthesis (33). We next examined a role of mTOR in CO-induced phosphorylation of p70 S6K and eIF-4E.…”

Section: Co-induced Increases In Hif-1␣ and Vegf Expression Arementioning

confidence: 99%

Carbon Monoxide Promotes VEGF Expression by Increasing HIF-1α Protein Level via Two Distinct Mechanisms, Translational Activation and Stabilization of HIF-1α Protein

Choi

Kim

Lee

et al. 2010

Journal of Biological Chemistry

138

132

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“…If for example TLK1/1B is the main H3 kinase involved in a “chromosomal response” to DNA damage, then ATM-mediated inhibition of TLK1 (see below) is expected to result in a loss of H3 phosphorylation by endogenous phosphatases and in altered kinetics of chromatin assembly during replication and/or repair. It is possible that physiologically the increased TLK1B synthesis following IR [56] can help offset the loss of TLK activity resulting from IR and restore appropriate levels of H3P later on during the recovery. The reduction of H3P following genotoxic stress (IR) was previously reported also by another group [57].…”

Section: General Information On Tousled-like Kinasesmentioning

confidence: 99%

“…Instead, we have independently cloned the TLK1B splice variant with a completely different screen, based upon polysomal redistribution of weakly translated transcripts that become preferentially recruited upon overexpression of eIF4E [8]. We subsequently found that TLK1B is synthesized efficiently in several cell lines overexpressing the translation factor/oncogene eIF4E, and we then presented several lines of evidence to confirm its translational regulation, particularly after genotoxic stress [56]. The significance of this translational regulation is discussed later when I emphasize the role of TLKs in DNA repair and protection from genotoxic agents, including IR and UV.…”

Section: Tlks In Man As Guardians Of Genome Stability and Their mentioning

confidence: 99%

The Tousled-Like Kinases as Guardians of Genome Integrity

Benedetti

2012

ISRN Molecular Biology

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The Tousled-like kinases (TLKs) function in processes of chromatin assembly, including replication, transcription, repair, and chromosome segregation. TLKs interact specifically (and phosphorylate) with the chromatin assembly factor Asf1, a histone H3-H4 chaperone, histone H3 itself at Ser10, and also Rad9, a key protein involved in DNA repair and cell cycle signaling following DNA damage. These interactions are believed to be responsible for the action of TLKs in double-stranded break repair and radioprotection and also in the propagation of the DNA damage response. Hence, I propose that TLKs play key roles in maintenance of genome integrity in many organisms of both kingdoms. In this paper, I highlight key issues of the known roles of these proteins, particularly in the context of DNA repair (IR and UV), their possible relevance to genome integrity and cancer development, and as possible targets for intervention in cancer management.

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“…Briefly, Rh30 or Rh1 cells grown in 100-mm dishes in serum-free DMEM medium were pretreated with or without rapamycin (100 ng/ml) in the presence or absence of IGF-1 (10 ng/ml) for 24 h. Subsequently, the cells were washed with PBS twice, switched to 3 ml of Met/Cys-free DMEM (Mediatech) containing 10 M MG-132 (Calbiochem), a proteasome inhibitor (to prevent protein from degradation), and then pulsed with 0.3 mCi/ml [ 35 S]Met/Cys (MP Biomedicals, Solon, OH) for up to 4 h in the presence or absence of rapamycin (100 ng/ml) and IGF-1 (10 ng/ml), as described previously (36). Subsequently, the labeled cells were lysed in 50 mM Tris, pH 7.2, containing 150 mM NaCl, 1% sodium deoxycholate, 0.1% SDS, 1%Triton X-100, 10 mM NaF, 1 mM Na 3 VO 4 , and protease inhibitor mixture (1:1000, Sigma).…”

Section: Methodsmentioning

confidence: 99%

Rapamycin Inhibits Cytoskeleton Reorganization and Cell Motility by Suppressing RhoA Expression and Activity

Liu

Luo

Chen

et al. 2010

Journal of Biological Chemistry

122

106

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The mammalian target of rapamycin (mTOR) functions in cells at least as two complexes, mTORC1 and mTORC2. Intensive studies have focused on the roles of mTOR in the regulation of cell proliferation, growth, and survival. Recently we found that rapamycin inhibits type I insulin-like growth factor (IGF-1)-stimulated lamellipodia formation and cell motility, indicating involvement of mTOR in regulating cell motility. This study was set to further elucidate the underlying mechanism. Here we show that rapamycin inhibited protein synthesis and activities of small GTPases (RhoA, Cdc42, and Rac1), crucial regulatory proteins for cell migration. Disruption of mTORC1 or mTORC2 by down-regulation of raptor or rictor, respectively, inhibited the activities of these proteins. However, only disruption of mTORC1 mimicked the effect of rapamycin, inhibiting their protein expression. Ectopic expression of rapamycin-resistant and constitutively active S6K1 partially prevented rapamycin inhibition of RhoA, Rac1, and Cdc42 expression, whereas expression of constitutively hypophosphorylated 4E-BP1 (4EBP1-5A) or down-regulation of S6K1 by RNA interference suppressed expression of the GTPases, suggesting that both mTORC1-mediated S6K1 and 4E-BP1 pathways are involved in protein synthesis of the GTPases. Expression of constitutively active RhoA, but not Cdc42 and Rac1, conferred resistance to rapamycin inhibition of IGF-1-stimulated lamellipodia formation and cell migration. The results suggest that rapamycin inhibits cell motility at least in part by down-regulation of RhoA protein expression and activity through mTORC1-mediated S6K1 and 4E-BP1-signaling pathways.The mammalian target of rapamycin (mTOR), 3 a member of the phosphoinositide 3Ј-kinase-related kinase family, is a central controller of cell proliferation, growth, and survival (1). Rapamycin can form a complex with FK506 binding protein 12 and then bind mTOR, selectively inhibiting its kinase activity and function (1). Recently, two mTOR complexes (mTORC1 and mTORC2) have been identified in mammalian cells (1). mTORC1 is composed of mTOR, mLST8 (also termed G-protein ␤-subunit-like protein, G␤L, a yeast homolog of LST8), PRAS40 (proline-rich Akt substrate 40 kDa), and raptor (regulatory-associated protein of mTOR) and is rapamycin-sensitive (2-8). In response to growth factors and nutrients, mTORC1 regulates cell proliferation and growth by modulating many processes, including protein synthesis and ribosome biogenesis through downstream effectors like 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1) and S6K1 (ribosomal p70 S6 kinase 1) (1, 9). mTORC2 consists of mTOR, mLST8, mSin1 (mammalian stress-activated protein kinase-interacting protein 1), rictor (rapamycin-insensitive companion of mTOR), and protor (protein observed with rictor; also named PRR5 (proline-rich protein 5)), and is rapamycin-insensitive (10 -16). mTORC2 phosphorylates Akt and PKC, signals to small GTPases (RhoA and Rac1), and controls cytoskeleton organization (11,(17)(18)(19)(20). Most recent...

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Translation of the radioresistance kinase TLK1B is induced by γ-irradiation through activation of mTOR and phosphorylation of 4E-BP1

Cited by 54 publications

References 21 publications

Carbon Monoxide Promotes VEGF Expression by Increasing HIF-1α Protein Level via Two Distinct Mechanisms, Translational Activation and Stabilization of HIF-1α Protein

Carbon Monoxide Promotes VEGF Expression by Increasing HIF-1α Protein Level via Two Distinct Mechanisms, Translational Activation and Stabilization of HIF-1α Protein

The Tousled-Like Kinases as Guardians of Genome Integrity

Rapamycin Inhibits Cytoskeleton Reorganization and Cell Motility by Suppressing RhoA Expression and Activity

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