共查询到20条相似文献,搜索用时 15 毫秒
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Bardella C Olivero M Lorenzato A Geuna M Adam J O'Flaherty L Rustin P Tomlinson I Pollard PJ Di Renzo MF 《Molecular and cellular biology》2012,32(15):3081-3094
Loss-of-function mutations of the tumor suppressor gene encoding fumarase (FH) occur in individuals with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). We found that loss of FH activity conferred protection from apoptosis in normal human renal cells and fibroblasts. In FH-defective cells, both hypoxia-inducible factor 1α (HIF-1α) and HIF-2α accumulated, but they were not required for apoptosis protection. Conversely, AMP-activated protein kinase (AMPK) was activated and required, as evidenced by the finding that FH inactivation failed to protect AMPK-null mouse embryo fibroblasts (MEFs) and AMPK-depleted human renal cells. Activated AMPK was detected in renal cysts, which occur in mice with kidney-targeted deletion of Fh1 and in kidney cancers of HLRCC patients. In Fh1-null MEFs, AMPK activation was sustained by fumarate accumulation and not by defective energy metabolism. Addition of fumarate and succinate to kidney cells led to extracellular signal-regulated kinase 1/2 (ERK1/2) and AMPK activation, probably through a receptor-mediated mechanism. These findings reveal a new mechanism of tumorigenesis due to FH loss and an unexpected pro-oncogenic role for AMPK that is important in considering AMPK reactivation as a therapeutic strategy against cancer. 相似文献
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Ethel R. Pereira Karen Frudd Walid Awad Linda M. Hendershot 《The Journal of biological chemistry》2014,289(6):3352-3364
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Functional genetic screen for genes involved in senescence: role of Tid1, a homologue of the Drosophila tumor suppressor l(2)tid, in senescence and cell survival
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Tarunina M Alger L Chu G Munger K Gudkov A Jat PS 《Molecular and cellular biology》2004,24(24):10792-10801
We performed a genetic suppressor element screen to identify genes whose inhibition bypasses cellular senescence. A normalized library of fragmented cDNAs was used to select for elements that promote immortalization of rat embryo fibroblasts. Fragments isolated by the screen include those with homology to genes that function in intracellular signaling, cellular adhesion and contact, protein degradation, and apoptosis. They include mouse Tid1, a homologue of the Drosophila tumor suppressor gene l(2)tid, recently implicated in modulation of apoptosis as well as gamma interferon and NF-kappaB signaling. We show that GSE-Tid1 enhances immortalization by human papillomavirus E7 and simian virus 40 T antigen and cooperates with activated ras for transformation. Expression of Tid1 is upregulated upon cellular senescence in rat and mouse embryo fibroblasts and premature senescence of REF52 cells triggered by activated ras. In accordance with this, spontaneous immortalization of rat embryo fibroblasts is suppressed upon ectopic expression of Tid1. Modulation of endogenous Tid1 activity by GSE-Tid1 or Tid1-specific RNA interference alleviates the suppression of tumor necrosis factor alpha-induced NF-kappaB activity by Tid1. We also show that NF-kappaB sequence-specific binding is strongly downregulated upon senescence in rat embryo fibroblasts. We therefore propose that Tid1 contributes to senescence by acting as a repressor of NF-kappaB signaling. 相似文献
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AMPK is an AMP-activated protein kinase that plays an important role in regulating cellular energy homeostasis. Metabolic
stress, such as heat shock and glucose starvation, causes an energy deficiency in the cell and leads to elevated levels of
intracellular AMP. This results in the phosphorylation and activation of AMPK. LKB1, a tumor suppressor, has been identified
as an upstream kinase of AMPK. We found that in response to treatment with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside
(AICAR), the LKB1 deficient cancer cell line, HeLa, exhibited AMPK-α phosphorylation. This indicates the existence of an LKB1-independent
AMPK-α phosphorylation pathway. ATM is a protein that is deficient in the disease ataxia telangiectasia (A-T). We measured
the activation of AMPK by AICAR in the normal mouse embryo fibroblast cell line, A29, and the mouse cell line lacking the
ATM protein, A38. In A38 cells, the level of AICAR-induced AMPK-α phosphorylation was significantly lower than that found
in A29 cells. Furthermore, phosphorylation of AMPK in HeLa and A29 cells was inhibited by an ATM specific inhibitor, KU-55933.
Our results demonstrate that AICAR treatment could lead to phosphorylation of AMPK in an ATM-dependent and LKB1-independent
manner. Thus, ATM may function as a potential AMPK kinase in response to AICAR treatment. 相似文献
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Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels 总被引:1,自引:0,他引:1
Mungai PT Waypa GB Jairaman A Prakriya M Dokic D Ball MK Schumacker PT 《Molecular and cellular biology》2011,31(17):3531-3545
AMP-activated protein kinase (AMPK) is an energy sensor activated by increases in [AMP] or by oxidant stress (reactive oxygen species [ROS]). Hypoxia increases cellular ROS signaling, but the pathways underlying subsequent AMPK activation are not known. We tested the hypothesis that hypoxia activates AMPK by ROS-mediated opening of calcium release-activated calcium (CRAC) channels. Hypoxia (1.5% O(2)) augments cellular ROS as detected by the redox-sensitive green fluorescent protein (roGFP) but does not increase the [AMP]/[ATP] ratio. Increases in intracellular calcium during hypoxia were detected with Fura2 and the calcium-calmodulin fluorescence resonance energy transfer (FRET) sensor YC2.3. Antioxidant treatment or removal of extracellular calcium abrogates hypoxia-induced calcium signaling and subsequent AMPK phosphorylation during hypoxia. Oxidant stress triggers relocation of stromal interaction molecule 1 (STIM1), the endoplasmic reticulum (ER) Ca(2+) sensor, to the plasma membrane. Knockdown of STIM1 by short interfering RNA (siRNA) attenuates the calcium responses to hypoxia and subsequent AMPK phosphorylation, while inhibition of L-type calcium channels has no effect. Knockdown of the AMPK upstream kinase LKB1 by siRNA does not prevent AMPK activation during hypoxia, but knockdown of CaMKKβ abolishes the AMPK response. These findings reveal that hypoxia can trigger AMPK activation in the apparent absence of increased [AMP] through ROS-dependent CRAC channel activation, leading to increases in cytosolic calcium that activate the AMPK upstream kinase CaMKKβ. 相似文献
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Wolff NC Vega-Rubin-de-Celis S Xie XJ Castrillon DH Kabbani W Brugarolas J 《Molecular and cellular biology》2011,31(9):1870-1884
mTORC1 is a critical regulator of cell growth that integrates multiple signals and is deregulated in cancer. We previously reported that mTORC1 regulation by hypoxia involves Redd1 and the Tsc1/Tsc2 complex. Here we show that Redd1 induction by hypoxia is tissue dependent and that hypoxia signals are relayed to mTORC1 through different pathways in a tissue-specific manner. In the liver, Redd1 induction is restricted to the centrilobular area, and in primary hepatocytes, mTORC1 inhibition by hypoxia is independent of Redd1. Furthermore, Tsc1/Tsc2 and Arnt (Hif-1β) are similarly dispensable. Hypoxia signaling in hepatocytes involves Lkb1, AMP-activated protein kinase (AMPK), and raptor. Differences in signal relay extend beyond hypoxia and involve AMPK signaling. AMPK activation (using 5-aminoimidazole-4-carboxamide riboside [AICAR]) induces raptor phosphorylation and inhibits mTORC1 in both mouse embryo fibroblasts (MEFs) and hepatocytes, but whereas mTORC1 inhibition is Tsc1/Tsc2 dependent in MEFs, it is independent in hepatocytes. In liver cells, raptor phosphorylation is essential for both AMPK and hypoxia signaling. Thus, context-specific signals are required for raptor phosphorylation-induced mTORC1 inhibition. Our data illustrate a heretofore unappreciated topological complexity in mTORC1 regulation. Interestingly, topological differences in mTORC1 regulation by the tumor suppressor proteins Lkb1 and Tsc1/Tsc2 may underlie their tissue specificity of tumor suppressor action. 相似文献
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Goda N Ryan HE Khadivi B McNulty W Rickert RC Johnson RS 《Molecular and cellular biology》2003,23(1):359-369
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Bilton R Mazure N Trottier E Hattab M Déry MA Richard DE Pouysségur J Brahimi-Horn MC 《The Journal of biological chemistry》2005,280(35):31132-31140
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Obach M Navarro-Sabaté A Caro J Kong X Duran J Gómez M Perales JC Ventura F Rosa JL Bartrons R 《The Journal of biological chemistry》2004,279(51):53562-53570
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Keith R. Laderoute Joy M. Calaoagan Wan-ru Chao Dominc Dinh Nicholas Denko Sarah Duellman Jessica Kalra Xiaohe Liu Ioanna Papandreou Lidia Sambucetti Laszlo G. Boros 《The Journal of biological chemistry》2014,289(33):22850-22864
Rapid tumor growth can establish metabolically stressed microenvironments that activate 5′-AMP-activated protein kinase (AMPK), a ubiquitous regulator of ATP homeostasis. Previously, we investigated the importance of AMPK for the growth of experimental tumors prepared from HRAS-transformed mouse embryo fibroblasts and for primary brain tumor development in a rat model of neurocarcinogenesis. Here, we used triple-negative human breast cancer cells in which AMPK activity had been knocked down to investigate the contribution of AMPK to experimental tumor growth and core glucose metabolism. We found that AMPK supports the growth of fast-growing orthotopic tumors prepared from MDA-MB-231 and DU4475 breast cancer cells but had no effect on the proliferation or survival of these cells in culture. We used in vitro and in vivo metabolic profiling with [13C]glucose tracers to investigate the contribution of AMPK to core glucose metabolism in MDA-MB-231 cells, which have a Warburg metabolic phenotype; these experiments indicated that AMPK supports tumor glucose metabolism in part through positive regulation of glycolysis and the nonoxidative pentose phosphate cycle. We also found that AMPK activity in the MDA-MB-231 tumors could systemically perturb glucose homeostasis in sensitive normal tissues (liver and pancreas). Overall, our findings suggest that the contribution of AMPK to the growth of aggressive experimental tumors has a critical microenvironmental component that involves specific regulation of core glucose metabolism. 相似文献
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Alexander V. Zhdanov Ruslan I. Dmitriev Anna V. Golubeva Svetlana A. Gavrilova Dmitri B. Papkovsky 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013