ERK Crosstalks with 4EBP1 to Activate Cyclin D1 Translation during Quinol-Thioether–Induced Tuberous Sclerosis Renal Cell Carcinoma

Cohen, Jennifer D.; Gard, Jaime M.C.; Nagle, Raymond B.; Dietrich, Justin; Monks, Terrence J.; Lau, Serrine S.

doi:10.1093/toxsci/kfr203

Cited by 20 publications

(20 citation statements)

References 59 publications

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“…MTORC1 can increase cyclin D1 expression via inactivation of eukaryotic initiation factor 4E-binding protein 1. 60,61,67,68 Previously, the MTOR was the only pathway known to be involved in acquiring classic markers of a senescent phenotype, including cyclin D1 accumulation. For the first time, we added an additional pathway, the MAPK pathway that is required, for the acquisition of at least one hallmark of senescence: hyperaccumulation of cyclin D1.…”

Section: Discussionmentioning

confidence: 99%

MEK drives cyclin D1 hyperelevation during geroconversion

2013

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When the cell cycle becomes arrested, MTOR (mechanistic Target of Rapamycin) converts reversible arrest into senescence (geroconversion). Hyperexpression of cyclin D1 is a universal marker of senescence along with hypertrophy, beta-Gal staining and loss of replicative/regenerative potential (RP), namely, the ability to restart proliferation when the cell cycle is released. Inhibition of MTOR decelerates geroconversion, although only partially decreases cyclin D1. Here we show that in p21-and p16-induced senescence, inhibitors of mitogen-activated/extracellular signal-regulated kinase (MEK) (U0126, PD184352 and siRNA) completely prevented cyclin D1 accumulation, making it undetectable. We also used MEL10 cells in which MEK inhibitors do not inhibit MTOR. In such cells, U0126 by itself induced senescence that was remarkably cyclin D1 negative. In contrast, inhibition of cyclin-dependent kinase (CDK) 4/6 by PD0332991 caused cyclin D1-positive senescence in MEL10 cells. Both types of senescence were suppressed by rapamycin, converting it into reversible arrest. We confirmed that the inhibitor of CDK4/6 caused cyclin D1 positive senescence in normal RPE cells, whereas U0126 prevented cyclin D1 expression. Elimination of cyclin D1 by siRNA did not prevent other markers of senescence that are consistent with the lack of its effect on MTOR. Our data confirmed that a mere inhibition of the cell cycle was sufficient to cause senescence, providing MTOR was active, and inhibition of MEK partially inhibited MTOR in a cell-type-dependent manner. Second, hallmarks of senescence may be dissociated, and hyperelevated cyclin D1, a marker of hyperactivation of senescent cells, did not necessarily determine other markers of senescence. Third, inhibition of MEK was sufficient to eliminate cyclin D1, regardless of MTOR. In proliferating cells, MTOR (mechanistic Target of Rapamycin) stimulates cellular mass growth, whereas cyclins D and E initiate S-phase transition.1-4 Withdrawal of growth factors causes reversible cell-cycle arrest (quiescence) with low levels of cyclins and MTOR activity, reversible by re-addition of growth factors. In contrast, cell-cycle arrest in the presence of growth stimuli, which activate MTOR, leads to cellular senescence. 5,6 In other words, when the cell cycle is blocked, while growth-promoting pathways such as MTOR remain active, cells continue to grow in size and undergo senescence. A process of conversion from normal reversible arrest into senescence was named as gerogenic conversion (geroconversion).7 Cellular senescence is characterized by large flat morphology (hypertrophy), beta-Gal staining, very high levels of cyclins D1 and E, senescence-associated secretory phenotype and loss of replicative/regenerative potential (RP).7-12 Loss of RP means that cells cannot proliferate even when cell-cycle block is removed and cells re-enter the cell cycle.13,14 Rapamycin decreases hypertrophy and loss of RP, in a dose-dependent manner proportional to S6 dephosphorylation (a marker of MTORC1 activity). 15Other ...

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Section: Discussionmentioning

confidence: 99%

MEK drives cyclin D1 hyperelevation during geroconversion

2013

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“…Phosphorylation of 4E-BP leads to its dissociation from eIF4E, a key rate-limiting initiation factor for translation (18). Recently, the mTOR independent interaction of 4E-BP with the ERK/MAPK signaling pathway, which is differentially regulated in our mouse model, was discussed intensively (11,37). Several lines of evidence have suggested a role of oxidative stress in longevity.…”

Section: E500mentioning

confidence: 96%

Skeletal muscle uncoupling-induced longevity in mice is linked to increased substrate metabolism and induction of the endogenous antioxidant defense system

Keipert

Ost

Chadt

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Keipert S, Ost M, Chadt A, Voigt A, Ayala V, Portero-Otin M, Pamplona R, Al-Hasani H, Klaus S. Skeletal muscle uncouplinginduced longevity in mice is linked to increased substrate metabolism and induction of the endogenous antioxidant defense system. Am J Physiol Endocrinol Metab 304: E495-E506, 2013. First published December 31, 2012 doi:10.1152/ajpendo.00518.2012.-Ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) mitochondria increases lifespan considerably in high-fat diet-fed UCP1 Tg mice compared with wild types (WT). To clarify the underlying mechanisms, we investigated substrate metabolism as well as oxidative stress damage and antioxidant defense in SM of low-fatand high-fat-fed mice. Tg mice showed an increased protein expression of phosphorylated AMP-activated protein kinase, markers of lipid turnover (p-ACC, FAT/CD36), and an increased SM ex vivo fatty acid oxidation. Surprisingly, UCP1 Tg mice showed elevated lipid peroxidative protein modifications with no changes in glycoxidation or direct protein oxidation. This was paralleled by an induction of catalase and superoxide dismutase activity, an increased redox signaling (MAPK signaling pathway), and increased expression of stress-protective heat shock protein 25. We conclude that increased skeletal muscle mitochondrial uncoupling in vivo does not reduce the oxidative stress status in the muscle cell. Moreover, it increases lipid metabolism and reactive lipid-derived carbonyls. This stress induction in turn increases the endogenous antioxidant defense system and redox signaling. Altogether, our data argue for an adaptive role of reactive species as essential signaling molecules for health and longevity.uncoupling protein 1; AMP-activated protein kinase; oxidative stress; redox signaling; lipid metabolism AGING IS A VERY COMPLEX PROCESS driven by numerous molecular pathways and biochemical events. Regarding the relationship between energy metabolism and longevity, there is a hypothesis termed "uncoupling to survive," which suggests that increased mitochondrial uncoupling and thus increased energy expenditure might increase longevity by preventing the formation of reactive oxygen species (ROS) (6). Previously, we showed that transgenic (Tg) mice with an ectopic expression of the uncoupling protein 1 (UCP1) in skeletal muscle (UCP1 Tg mice) showed a delayed development of obesity, improved glucose tolerance, and a 42% increased median lifespan compared with their wild-type (WT) littermates when exposed to a high-fat diet (30). However, the molecular mechanisms for these beneficial health effects of skeletal muscle uncoupling are not yet clarified.One hallmark of UCP1 Tg mice is an increased insulin sensitivity independent of body weight. Insulin resistance plays a crucial part in the pathogenesis of the metabolic syndrome and is characterized by a reduced substrate metabolism and impaired defense against stress in skeletal muscle. Skeletal muscle (SM) uncoupling increases SM glucose uptake and activates the AMPactivated protein k...

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“…Inhibitor of S6K (PF478671) only slightly decreased levels of cyclin D1, indicating that effects of rapamycin on cyclin D1 accumulation may involve different pathways. In fact, it was shown that MTOR increases cyclin D1 through inactivation of 4EBP1 55 , 56 . We also investigated 2 inhibitors of p90 RSK (SL 0101-1 and BRD7389).…”

mentioning

confidence: 99%

S6K in geroconversion

Leontieva¹,

Demidenko

Blagosklonny³

2013

Cell Cycle

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Markers of cellular senescence depend in part on the MTOR (mechanistic target of rapamycin) pathway. MTOR participates in geroconversion, a conversion from reversible cell cycle arrest to irreversible senescence. Recently we demonstrated that hyper-induction of cyclin D1 during geroconversion was mostly dependent on MEK, whereas rapamycin only partially inhibited cyclin D1 accumulation. Here we show that, while not affecting cyclin D1, siRNA for p70S6K partially prevented loss of RP (replicative/regenerative potential) during p21-induced cell cycle arrest. Similarly, an inhibitor of p70 S6 kinase (PF-4708671) partially inhibited phosphorylation of S6 and preserved RP, while only marginally prevented cyclin D1 induction. Thus S6K and MEK play different roles in geroconversion.

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ERK Crosstalks with 4EBP1 to Activate Cyclin D1 Translation during Quinol-Thioether–Induced Tuberous Sclerosis Renal Cell Carcinoma

Cited by 20 publications

References 59 publications

MEK drives cyclin D1 hyperelevation during geroconversion

MEK drives cyclin D1 hyperelevation during geroconversion

Skeletal muscle uncoupling-induced longevity in mice is linked to increased substrate metabolism and induction of the endogenous antioxidant defense system

S6K in geroconversion

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