Compound C inhibits clonal expansion of preadipocytes by increasing p21 level irrespectively of AMPK inhibition

Nam, Minwoo; Lee, Woo Hyung; Bae, Eun Ju; Kim, Sang Geon

doi:10.1016/j.abb.2008.07.029

Cited by 45 publications

(42 citation statements)

References 35 publications

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“…Thus, compound C prevents G 1 to S phase transition by disrupting the expression of multiple cell cycle regulatory proteins. Our finding that compound C increases p21 expression is in agreement with another study in preadipocytes and probably reflects the ability of compound C to stabilize the protein (Nam et al, 2008).…”

Section: Discussionsupporting

confidence: 82%

“…Although studies indicate that compound C blocks the proliferation of nonvascular cells, its direct action on vascular SMC growth was not known (Nam et al, 2008;Vucicevic et al, 2009). In the current study, we found that compound C is a robust inhibitor of vascular SMC proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…Of interest, studies indicate that compound C exerts a potent antiproliferative effect in both rodent and human tumor cell lines via AMPK-dependent and -independent mechanisms (Vucicevic et al, 2009). In addition, compound C has been demonstrated to block the clonal expansion of preadipocytes irrespective of AMPK inhibition (Nam et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Compound C Inhibits Vascular Smooth Muscle Cell Proliferation and Migration in an AMP-Activated Protein Kinase-Independent Fashion

Peyton

Yan²,

Yates³

et al. 2011

J Pharmacol Exp Ther

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6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine (compound C) is a cell-permeable pyrrazolopyrimidine derivative that acts as a potent inhibitor of AMPactivated protein kinase (AMPK). Although compound C is often used to determine the role of AMPK in various physiological processes, it also evokes AMPK-independent actions. In the present study, we investigated whether compound C influences vascular smooth muscle cell (SMC) function through the AMPK pathway. Treatment of rat aortic SMCs with compound C (0.02-10 M) inhibited vascular SMC proliferation and migration in a concentration-dependent fashion. These actions of compound C were not mimicked or affected by silencing AMPK␣ expression or infecting SMCs with an adenovirus expressing a dominant-negative mutant of AMPK. In contrast, the pharmacological activator of AMPK 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside inhibited the proliferation and migration of SMCs in a manner that was strictly dependent on AMPK activity. Flow cytometry experiments revealed that compound C arrested SMCs in the G 0 /G 1 phase of the cell cycle, and this was associated with a decrease in cyclin D1 and cyclin A protein expression and retinoblastoma protein phosphorylation and an increase in p21 protein expression. Finally, local perivascular delivery of compound C immediately after balloon injury of rat carotid arteries markedly attenuated neointima formation. These studies identify compound C as a novel AMPKindependent regulator of vascular SMC function that exerts inhibitory effects on SMC proliferation and migration and neointima formation after arterial injury. Compound C represents a potentially new therapeutic agent in treating and preventing occlusive vascular disease.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Compound C Inhibits Vascular Smooth Muscle Cell Proliferation and Migration in an AMP-Activated Protein Kinase-Independent Fashion

Peyton

Yan²,

Yates³

et al. 2011

J Pharmacol Exp Ther

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“…However, the activity of at least 10 kinases is inhibited by Compound C with lower IC 50 values than AMPK (1), and several studies have reported inhibition of various biological events by Compound C independently of AMPK inhibition (6,18). Nevertheless, together with the genetic evidence provided in this study, the support for a role of AMPK becomes stronger.…”

Section: Discussionmentioning

confidence: 52%

Genetic disruption of AMPK signaling abolishes both contraction- and insulin-stimulated TBC1D1 phosphorylation and 14-3-3 binding in mouse skeletal muscle

Pehmøller

Treebak²,

Birk³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

145

143

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TBC1D1 is a Rab-GTPase-activating protein (GAP) known to be phosphorylated in response to insulin, growth factors, pharmacological agonists that activate 5′-AMP-activated protein kinase (AMPK), and muscle contraction. Silencing TBC1D1 in L6 muscle cells by siRNA increases insulin-stimulated GLUT4 translocation, and overexpression of TBC1D1 in 3T3-L1 adipocytes with low endogenous TBC1D1 expression inhibits insulin-stimulated GLUT4 translocation, suggesting a role of TBC1D1 in regulating GLUT4 translocation. Aiming to unravel the regulation of TBC1D1 during contraction and the potential role of AMPK in intact skeletal muscle, we used EDL muscles from wild-type (WT) and AMPK kinase dead (KD) mice. We explored the site-specific phosphorylation of TBC1D1 Ser237 and Thr596 and their relation to 14-3-3 binding, a proposed mechanism for regulation of GAP function of TBC1D1. We show that muscle contraction increases 14-3-3 binding to TBC1D1 as well as phosphorylation of Ser237 and Thr596 in an AMPK-dependent manner. AMPK activation by AICAR induced similar Ser237 and Thr596 phosphorylation of, and 14-3-3 binding to, TBC1D1 as muscle contraction. Insulin did not increase Ser237 phosphorylation or 14-3-3 binding to TBC1D1. However, insulin increased Thr596 phosphorylation, and intriguingly this response was fully abolished in the AMPK KD mice. Thus, TBC1D1 is differentially regulated in response to insulin and contraction. This study provides genetic evidence to support an important role for AMPK in regulating TBC1D1 in response to both of these physiological stimuli.

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“…This is not surprising, as compound C has previously been reported to exert AMPK-independent biological effects, including inhibition of bone morphogenetic protein signaling, 62 blockade of hypoxia inducible factor-1 activation, 63 and induction of cell cycle regulator p21. 64 In contrast to expectations that induction of autophagy might be used as a "magic bullet" for the treatment of apoptosis-resistant cancers, 9 a large body evidence supports the hypothesis that tumor cells in certain conditions might actually use autophagy to evade therapy-induced death. Accordingly, inhibition of autophagy, particularly at a late stage, sensitized cancer cells to apoptosis phospho-Src (ab4816), Src (ab47405; Abcam) or p62 (647702; Biolegend) and peroxidase-conjugated goat anti-rabbit IgG (Jackson ImmunoResearch Laboratories, 111-035-003) as the secondary antibody, specific protein bands were visualized using Amersham ECL reagent (GE Healthcare, RPN2109).…”

Section: Methodsmentioning

confidence: 96%

Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway

Vučićević¹,

Misirkić²,

Janjetović³

et al. 2011

Autophagy

214

161

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Compound C inhibits clonal expansion of preadipocytes by increasing p21 level irrespectively of AMPK inhibition

Cited by 45 publications

References 35 publications

Compound C Inhibits Vascular Smooth Muscle Cell Proliferation and Migration in an AMP-Activated Protein Kinase-Independent Fashion

Compound C Inhibits Vascular Smooth Muscle Cell Proliferation and Migration in an AMP-Activated Protein Kinase-Independent Fashion

Genetic disruption of AMPK signaling abolishes both contraction- and insulin-stimulated TBC1D1 phosphorylation and 14-3-3 binding in mouse skeletal muscle

Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway

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