IGF-1 phosphorylates AMPK-α subunit in ATM-dependent and LKB1-independent manner

Suzuki, Atsushi; Kusakai, Gen-ichi; Kishimoto, Atsuhiro; Shimojo, Yosuke; Ogura, Tsutomu; Lavin, Martin F.; Esumi, Hiroyasu

doi:10.1016/j.bbrc.2004.09.145

Cited by 80 publications

(79 citation statements)

References 36 publications

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“…respond to other stresses that do not involve DNA damage (Bakkenist and Kastan, 2003;Suzuki et al, 2004;Hunt et al, 2007). To determine whether deregulated E2F3a activity causes DNA breaks as the mechanism for activating ATM, we used the single-cell gel electrophoresis (comet) assay.…”

Section: Resultsmentioning

confidence: 99%

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Transgenic expression of E2F3a causes DNA damage leading to ATM-dependent apoptosis

et al. 2008

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Many early stage human tumors display markers of a DNA-damage response (DDR), including ataxia telangiectasia mutated (ATM) kinase activation. This suggests that DNA damage accumulates during the process of carcinogenesis and that the ATM-dependent response to this damage may function to suppress cancer progression. The E2F3a transcription factor plays an important role in regulating cell proliferation and is amplified in a subset of human cancers. Similar to human premalignant lesions, we find activated ATM and other markers of the DDR in the hyperplastic epidermis of transgenic mice expressing E2F3a through a keratin 5 (K5) promoter. Primary keratinocytes from K5 E2F3a transgenic mice contain increased levels of DNA breaks compared to wild-type cells. E2F3a overexpression also induced DNA damage in primary human fibroblasts that was inhibited by blocking DNA replication. The absence of ATM impaired apoptosis induced by E2F3a and treating K5 E2F3a transgenic mice with caffeine, an inhibitor of ATM and Rad3-related (ATR), promoted skin tumor development. These findings demonstrate that the deregulated expression of E2F3a causes DNA damage under physiological conditions and indicate that the ATM-dependent response to this damage is important for the induction of apoptosis and tumor suppression.

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Section: Resultsmentioning

confidence: 99%

“…In addition, ATM activation can also induce apoptosis or senescence, if DNA damage is persistent. ATM function is best characterized in the response to DNA double-strand breaks but it is now known that ATM can also respond to other types of cellular stress (Bakkenist and Kastan, 2003;Suzuki et al, 2004;Hunt et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Transgenic expression of E2F3a causes DNA damage leading to ATM-dependent apoptosis

et al. 2008

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“…AMPK is a highly conserved enzyme which senses changes in the cellular AMP/ ATP ratio, and once activated switches on catabolic, ATPproducing processes, and switches off ATP-consuming anabolic processes (Kola et al 2006). AMPK is activated by phosphorylation on the Thr172 residue by upstream kinases LKB1 and calmodulin kinase kinase 2 (CaMKK2; Hawley et al 2005, Woods et al 2005, but recent data also suggest a role in certain circumstances for transforming growth factorb-activated kinase (Suzuki et al 2004, Woods et al 2005, Momcilovic et al 2006) and ataxiatelangiectasia mutated gene (Suzuki et al 2004). Recent data suggest that increased AMP does not directly promote phosphorylation of Thr172 by upstream kinases but rather inhibits the dephosphorylation of AMPK by protein phosphatase-2C-a (PP2C-a; Sanders et al 2007.…”

Section: Ampk and Ghrelinmentioning

confidence: 99%

Shedding light on the intricate puzzle of ghrelin's effects on appetite regulation

Kola¹,

Korbonits²

2009

Journal of Endocrinology

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Ghrelin, a hormone primarily produced by the stomach, has a wide range of metabolic and non-metabolic effects. It also stimulates food intake through activation of various hypothalamic and brain stem neurons. A series of recent studies have explored the intracellular mechanisms of the appetite-inducing effect of ghrelin in the hypothalamus, shedding light on the intricate mechanisms of appetite regulation. AMP-activated protein kinase (AMPK) is a key metabolic enzyme involved in appetite regulation.Calmodulin kinase kinase 2 (CaMKK2) has been identified as an upstream kinase of AMPK and a key mediator in the effect of ghrelin on AMPK activity. The fatty acid pathway, hypothalamic mitochondrial respiration, and uncoupling protein 2 have been outlined as downstream targets of AMPK and mediators of ghrelin's appetite stimulating effect. This short overview summarises the present data in this field.

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“…The expression levels of wild-type and mutant Stk11/ Lkb1 were comparable. The Thr-172 phosphorylation of AMPK was not completely abolished in the presence of mutant Stk11/Lkb1 because Stk11/Lkb1 is the dominant but not the only upstream regulator of AMPK (Shaw et al, 2004a, b;Suzuki et al, 2004). Figure 1 Genetic alterations identified in STK11LKB1 exons in 15 HNSCC specimens.…”

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confidence: 99%

A novel mutation of STK11/LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma

et al. 2006

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To investigate whether genetic alteration of the STK11 (serine/threonine kinase 11)/LKB1 tumor-suppressor gene is involved in the carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the entire encoding exons and flanking intronic sequences of the STK11/ LKB1 gene were analysed with direct genomic sequencing of 15 HNSCC specimens. A novel missense mutation with presumed loss of heterozygosity (LOH) and 10 polymorphisms were identified in these samples. The novel mutation of STK11/LKB1 at nucleotide position 613 G-A, which causes the amino-acid substitution from alanine to threonine at residue 205 within the catalytic kinase domain, was identified in cell line RPMI 2650. To further determine whether this point mutation affects the gene function, constructs of the wild type and A205T mutant of the STK11/LKB1 gene expression vectors were created and transfected into RPMI 2650 cells. Our results showed that the reintroduction of the wild-type but not the mutant STK11/LKB1 construct into RPMI 2650 cells induced suppression of the cell growth. The mutation also affected the kinase activity of the Stk11/Lkb1 protein. This led us to conclude that the A205T point mutation of the STK11/ LKB1 gene produces functionally inactive proteins. This is the first described mutation of the STK11/LKB1 gene in HNSCC. While the mutation frequency of the STK11/ LKB1 gene in HNSCC remains to be determined in future studies, our data strongly suggests that STK11/LKB1 is involved in the carcinogenesis of HNSCC.

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IGF-1 phosphorylates AMPK-α subunit in ATM-dependent and LKB1-independent manner

Cited by 80 publications

References 36 publications

Transgenic expression of E2F3a causes DNA damage leading to ATM-dependent apoptosis

Transgenic expression of E2F3a causes DNA damage leading to ATM-dependent apoptosis

Shedding light on the intricate puzzle of ghrelin's effects on appetite regulation

A novel mutation of STK11/LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma

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