Adenosine Monophosphate-Activated Protein Kinase Suppresses Vascular Smooth Muscle Cell Proliferation Through the Inhibition of Cell Cycle Progression

Igata, Motoyuki; Motoshima, Hiroyuki; Tsuruzoe, Kaku; Kojima, Kanou; Matsumura, Takeshi; Kondo, Tatsuya; Taguchi, Tetsuya; Nakamaru, Kazuhiko; Yano, Masato; Kukidome, Daisuke; Matsumoto, Kazuya; Toyonaga, Tetsushi; Asano, Tomohiko; Nishikawa, Takeshi; Araki, Eiichi

doi:10.1161/01.res.0000185823.73556.06

Cited by 227 publications

(173 citation statements)

References 45 publications

(55 reference statements)

Supporting

Mentioning

153

Contrasting

Order By: Relevance

“…Furthermore, the present study revealed that the phosphorylation of endogenous p53-Ser 15 was increased by LKB1 overexpression or AMPK activation, suggesting that p53-Ser 15 phosphorylation, a modification essential for p53 stabilization, may be involved in p21/WAF1 upregulation. The results of the present study are consistent with previous reports indicating that AMPK induces phosphorylation of p53-Ser15 in hepatoma HepG2 cells (21), mouse embryonic fibroblasts (22), human aortic smooth muscle cells and rabbit aortic strips (23). Other kinases have been demonstrated to phosphorylate p53 at Ser 15 , including ATM and ATR serine/threonine kinases, as they also target p53 at this site (24).…”

Section: Discussionsupporting

confidence: 93%

Liver kinase B1/adenosine monophosphate‑activated protein kinase signaling axis induces p21/WAF1 expression in a p53‑dependent manner

Xiao

Sun

et al. 2018

Oncol Lett

View full text Add to dashboard Cite

Abstract. Liver kinase B1 (LKB1) encodes a serine/threonine kinase and functions as a tumor suppressor. LKB1 loss-of-function somatic mutations are frequently observed in sporadic types of cancer, particularly in lung cancer. Ectopic LKB1 induces growth arrest by upregulating p21/cyclin dependent kinase inhibitor 1A (WAF1) in LKB1 deficient cervical and melanoma cancer cell lines. However, the underlying molecular mechanism remains to be elucidated. The present study built upon previous observations by confirming that the ectopic expression level of LKB1 significantly reduced colony formation of LKB1-deficient lung cancer cells.Mechanistically, the present study demonstrated that LKB1 overexpression significantly induced p21/WAF1 expression in a kinase-dependent manner. Conversely, LKB1 stable knockdown resulted in a decrease in p21/WAF1 expression level in colon cancer cells. In addition, it was revealed that pharmacological activation of adenosine monophosphate protein kinase (AMPK) by 2-deoxyglucose significantly increased the p21/WAF1 expression level, suggesting that AMPK acts downstream of LKB1 to induce p21/WAF1 expression. Furthermore, the present study demonstrated that functional p53 was required for p21/WAF1 induction by LKB1. Phosphorylation of p53-Ser 15 was increased by ectopic LKB1 or AMPK activation. Taken together, these results suggested that LKB1 acts via its substrate, AMPK, to upregulate p21/WAF1 expression in a p53-dependent manner. Therefore, the present study identified an important signaling axis, providing novel molecular insights into the tumor suppressor role of LKB1.

show abstract

Section: Discussionsupporting

confidence: 93%

Liver kinase B1/adenosine monophosphate‑activated protein kinase signaling axis induces p21/WAF1 expression in a p53‑dependent manner

Xiao

Sun

et al. 2018

Oncol Lett

View full text Add to dashboard Cite

show abstract

“…As AMPK phosphorylation has been linked to inhibition of SMC proliferation (Nagata et al 2004, Igata et al 2005, activation of AMPK would not be expected if adiponectin and globular adiponectin stimulate SMC proliferation. On the other hand, AMPK phosphorylation occurred upon treatment with PDGF, a potent mitogen (Figs 2 and 3), which suggests that AMPK activation may not be strictly associated with growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…4A). AMPK activation has been reported to block DNA synthesis (Igata et al 2005), a response that is inconsistent with the actions of a potent mitogen-like PDGF (Fig. 1A).…”

Section: Activation Of Ampk Does Not Inhibit Dna Synthesismentioning

confidence: 96%

Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form

Fuerst¹,

Taylor²,

Wright³

et al. 2012

Journal of Endocrinology

View full text Add to dashboard Cite

Accelerated atherosclerosis is the primary cardiovascular manifestation of diabetes and correlates inversely with levels of circulating adiponectin, an anti-atherosclerotic adipokine that declines in diabetes. We therefore initiated a study to examine the mechanisms by which adiponectin, a hormone released from adipose tissue, influences the proliferation of vascular smooth muscle cells (SMCs). Addition of adiponectin to quiescent porcine coronary artery SMCs increased both protein and DNA synthesis and concurrently activated ERK1/2 and Akt. By contrast, globular adiponectin, a truncated form of this protein, exhibited anti-mitogenic properties as indicated by the inhibition of protein and DNA synthesis in SMCs stimulated with platelet-derived growth factor (PDGF). Whereas globular adiponectin did not stimulate growth-related signal transduction pathways, it was able to block the PDGF-dependent phosphorylation of eukaryotic elongation factor 2 kinase, a regulator of protein synthesis. Proteolysis of adiponectin with trypsin, which produces globular adiponectin, reversed the growth-stimulating actions of the undigested protein. As the existence of globular adiponectin remains controversial, western blotting was used to establish its presence in rat serum. We found that globular adiponectin was detectable in rat serum, but this result was not obtained with all antibodies. The contrasting properties of adiponectin and its globular form with respect to SMC proliferation suggest that protection against atherosclerosis may therefore be mediated, in part, by the level of globular adiponectin.

show abstract

“…36 As mentioned above, in the endothelial cell, AMPK activates the PI3K-Akt system, and it has been shown that this antiapoptotic effect takes place through the PI3K-Akt axis. 41 The vascular smooth muscle. We have shown that the growth of the vascular smooth muscle cell stimulated by angiotensin II (AngII) can be inhibited by the activation of AMPK.…”

Section: Function In the Vasculaturementioning

confidence: 99%

“…In the wire injury model of the rat femoral artery, if AMPK is continuously activated by AICAR injection, neointima formation is significantly inhibited, and AMPK inhibits the growth of the vascular smooth muscle, even in vivo. Igata et al 41 revealed that AMPK increases p21cip, which is the cyclin-dependent kinase inhibitor, through inhibition of the phosphorylation of the retinoblastoma gene product (Rb), as well as increased expression/phosphorylation enhancement of p53, and inhibits the cell cycle of the vascular smooth muscle at G1/S. Recently, the presence of a mechanism has shown that the activation of thromboxane A2 receptor promotes hypertrophy of the vascular smooth muscle and activates AMPK ROS dependently.…”

Section: Function In the Vasculaturementioning

confidence: 99%

The role of AMP-activated protein kinase in the cardiovascular system

Nagata

Hirata

2009

Hypertens Res

View full text Add to dashboard Cite

It has recently been recognized that adiponectin protects the vasculature and prevents atherosclerotic change through AMP-activated protein kinase (AMPK) activation, and some of its molecular mechanisms have been clarified. AMPK, which might be a therapeutic target of metabolic abnormality, is a serine-threonine kinase, heterotrimer protein composed of three subunits of a, b and c. It is activated by an upper kinase LKB1 and an increase in the AMP/ATP ratio. Some anabolic enzymes are directly phosphorylated and inhibited, suggesting that AMPK suppresses ATP consumption by negatively regulating the synthetic pathway. The LKB1-AMPK pathway is pivotal for controlling cellular polarity and mitosis. Furthermore, AMPK has been associated with cellular autophagy. AMPK activation could induce autophagy and prolong a period leading to cell apoptosis. Apoptosis under anoxic conditions was decreased when newly constructed, constitutively active mutants of AMPK-a were overexpressed in vascular endothelial cells. AMPK could inhibit the growth of vascular smooth muscle through MEK-ERK pathway inhibition. After ischemia reperfusion, dominant-negative AMPK overexpression inhibits cardiac function through the suppression of glucose uptake and fatty acid b-oxidation in cardiac myocytes. Cardiac hypertrophy with accumulation of glycogen granules because of gene mutation of c2 associated with the Wolff-Parkinson-White syndrome has been considered an activated type in most cases. It is necessary to clarify the tissue-specific and stress-specific activation mechanism of AMPK.

show abstract

Adenosine Monophosphate-Activated Protein Kinase Suppresses Vascular Smooth Muscle Cell Proliferation Through the Inhibition of Cell Cycle Progression

Cited by 227 publications

References 45 publications

Liver kinase B1/adenosine monophosphate‑activated protein kinase signaling axis induces p21/WAF1 expression in a p53‑dependent manner

Liver kinase B1/adenosine monophosphate‑activated protein kinase signaling axis induces p21/WAF1 expression in a p53‑dependent manner

Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form

The role of AMP-activated protein kinase in the cardiovascular system

Contact Info

Product

Resources

About