Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence suggests that ovarian hormones contribute to altered function of skeletal muscle, however the signaling processes thought to regulate muscle function remain undefined in females. Thus, the purpose of this investigation is to determine if ovarian hormone status is critical for contraction-induced activation of AMPK or MAPK in skeletal muscle. Female mice were divided into two groups, ovariectomy (OVX) and SHAM, which were then subjected to in situ isometric contractile protocols. AMPK, ERK 1/2, p38, and JNK phosphorylation were measured in the control and contracting limb. In the in situ protocol, OVX muscles were significantly more resistant to fatigue compared to the SHAM animals. In addition, the muscles from OVX mice demonstrated significantly lower levels of normalized AMPK phosphorylation at rest. AMPK phosphorylation was not increased in the muscles from SHAM mice after the in situ contractile protocol, while the OVX demonstrated significant increases in AMPK phosphorylation. After contraction, normalized ERK2 phosphorylation was significantly higher in the OVX group compared to the SHAM group. Both p38 and JNK phosphorylation increased in response to contraction; but no group differences were detected. A second set of SHAM and OVX animals were subjected to fatigue stimulated under in vitro conditions. Significant increases in AMPK and ERK2 phosphorylation were detected, but no differences were found between groups. In conclusion, removal of the ovaries results in different responses to contraction-induced changes in phosphorylation of AMPK and ERK2 in female mice and suggests hormones secreted from the ovaries significantly impacts cellular signaling in skeletal muscle.
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PMID:Changes in contraction-induced phosphorylation of AMP-activated protein kinase and mitogen-activated protein kinases in skeletal muscle after ovariectomy. 1925 49

Beta-Guanadinopropionic acid (beta-GPA) feeding leads to reductions in skeletal muscle phosphagen concentrations and has been used as a tool with which to study the effects of energy charge on skeletal muscle metabolism. Supplementing standard rodent diets with beta-GPA leads to increases in mitochondrial enzyme content in fast but not slow-twitch muscles from male rats. Given this apparent discrepancy between muscle types we used beta-GPA feeding as a model to study signaling pathways involved in mitochondrial biogenesis. We hypothesized that beta-GPA feeding would result in a preferential activation of p38 MAPK and AMPK signaling and reductions in RIP140 protein content in triceps but not soleus muscle. Despite similar reductions in high-energy phosphate concentrations, 6 wk of beta-GPA feeding led to increases in mitochondrial proteins in triceps but not soleus muscles. Differences in the response of mitochondrial proteins to beta-GPA feeding did not seem to be related to a differential activation of p38 MAPK and AMPK signaling pathways or discrepancies in the induction of PPARgamma coactivator (PGC)-1alpha and -1beta. The protein content and expression of the nuclear corepressor RIP140 was reduced in triceps but not soleus muscle. Collectively our results indicate that chronic reductions in high-energy phosphates lead to the activation of p38 MAPK and AMPK signaling and increases in the expression of PGC-1alpha and -1beta in both soleus and triceps muscles. The lack of an effect of beta-GPA feeding on mitochondrial proteins in the soleus muscles could be related to a fiber type-specific effect of beta-GPA on RIP140 protein content.
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PMID:Muscle-specific differences in the response of mitochondrial proteins to beta-GPA feeding: an evaluation of potential mechanisms. 1931 15

Epidemiological and experimental evidence has supported the notion that solar ultraviolet (UV) radiation is the leading cause of skin cell damage and skin cancer. Non-melanoma skin cancer, one of the malignancies with the most rapidly increasing incidence, is suggested to be directly related to the total exposure to solar UV light. Over the past few years, the mechanisms of cellular responses to UV radiation have received unprecedented attention. Understanding how skin cells respond to UV radiation will undoubtedly help decipher what goes wrong in a variety of clinical skin disorders including skin cancer and will facilitate the development of novel therapeutic strategies. In the past decade, studies have established that UV radiation induces multifarious signal transduction pathways, some of which lead to apoptotic cell death, while others protect against this process. In this review, we summarize some of the most recent progresses regarding the involvement of multiple signal pathways in UV radiation-induced apoptosis in skin cells, especially in keratinocytes. These pathways include pro-apoptosis components such as MAPK, AMPK, and p53 as well as pro-survival components, namely, AKT and mTORC complexes.
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PMID:Parameters of protection against ultraviolet radiation-induced skin cell damage. 1936 Jul 45

We investigated cardiac hypertrophy elicited by rosiglitazone treatment at the level of protein synthesis/degradation, mTOR, MAPK and AMPK signalling pathways, cardiac function and aspects of carbohydrate/lipid metabolism. Hearts of rats treated or not with rosiglitazone (15 mg/kg day) for 21 days were evaluated for gene expression, protein synthesis, proteasome and calpain activities, signalling pathways, and function by echocardiography. Rosiglitazone induced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectin, reduced heart rate and increased stroke volume. Rosiglitazone robustly increased heart glycogen content ( approximately 400%), an effect associated with increases in glycogenin and UDPG-PPL mRNA levels and glucose uptake, and a reduction in glycogen phosphorylase expression and activity. Cardiac triglyceride content, lipoprotein lipase activity and mRNA levels of enzymes involved in fatty acid oxidation were also reduced by the agonist. Rosiglitazone-induced cardiac hypertrophy was associated with an increase in myofibrillar protein content and turnover (increased synthesis and an enhancement of calpain-mediated myofibrillar degradation). In contrast, 26S beta5 chymotryptic proteasome activity and mRNA levels of 20S beta2 and beta5 and 19S RPN 2 proteasome subunits along with the ubiquitin ligases atrogin and CHIP were all reduced by rosiglitazone. These morphological and biochemical changes were associated with marked activation of the key growth-promoting mTOR signalling pathway, whose pharmacological inhibition with rapamycin completely blocked cardiac hypertrophy induced by rosiglitazone. The study demonstrates that both arms of protein balance are involved in rosiglitazone-induced cardiac hypertrophy, and establishes the mTOR pathway as a novel important mediator therein.
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PMID:Rosiglitazone-induced heart remodelling is associated with enhanced turnover of myofibrillar protein and mTOR activation. 1939 13

Triple negative (TN) breast cancer is more frequent in women who are obese or have type II diabetes, as well as young women of color. These cancers do not express receptors for the steroid hormones estrogen or progesterone, or the type II receptor tyrosine kinase (RTK) Her-2 but do have upregulation of basal cytokeratins and the epidermal growth factor receptor (EGFR). These data suggest that aberrations of glucose and fatty acid metabolism, signaling through EGFR and genetic factors may promote the development of TN cancers. The anti-type II diabetes drug metformin has been associated with a decreased incidence of breast cancer, although the specific molecular subtypes that may be reduced by metformin have not been reported. Our data indicates that metformin has unique anti-TN breast cancer effects both in vitro and in vivo. It inhibits cell proliferation (with partial S phase arrest), colony formation and induces apoptosis via activation of the intrinsic and extrinsic signaling pathways only in TN breast cancer cell lines. At the molecular level, metformin increases P-AMPK, reduces P-EGFR, EGFR, P-MAPK, P-Src, cyclin D1 and cyclin E (but not cyclin A or B, p27 or p21), and induces PARP cleavage in a dose- and time-dependent manner. These data are in stark contrast to our previously published biological and molecular effects of metformin on luminal A and B, or Her-2 type breast cancer cells. Nude mice bearing tumor xenografts of the TN line MDA-MB-231, treated with metformin, show significant reductions in tumor growth (p = 0.0066) and cell proliferation (p = 0.0021) as compared to untreated controls. Metformin pre-treatment, before injection of MDA-MB-231 cells, results in a significant decrease in tumor outgrowth and incidence. Given the unique anti-cancer activity of metformin against TN disease, both in vitro and in vivo, it should be explored as a therapeutic agent against this aggressive form of breast cancer.
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PMID:Metformin induces unique biological and molecular responses in triple negative breast cancer cells. 1971 81

Cancer is a hyperproliferative disorder that is usually treated by chemotherapeutic agents that are toxic not only to tumor cells but also to normal cells, so these agents produce major side effects. In addition, these agents are highly expensive and thus not affordable for most. Moreover, such agents cannot be used for cancer prevention. Traditional medicines are generally free of the deleterious side effects and usually inexpensive. Curcumin, a component of turmeric (Curcuma longa), is one such agent that is safe, affordable, and efficacious. How curcumin kills tumor cells is the focus of this review. We show that curcumin modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills tumor cells, and not normal cells, is also described in detail.
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PMID:Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? 1959 Sep 64

This study reveals that the activation of either PPARalpha (WY 14643) or PPARbeta (GW0742) each induce the translocation of FAT/CD36 from an intracellular pool(s) to the plasma membrane, while PPARbeta also induces the subcellular redistribution of FABPpm(Got2) to the plasma membrane. In contrast, activation of PPARgamma failed to induce the subcellular redistribution of FAT/CD36 and FABPpm. These PPARalpha-, and PPARbeta-induced changes in the plasmalemmal content of these fatty acid transporters were associated with the concurrent upregulation of fatty acid triacylglycerol esterification (PPARbeta) and oxidation (PPARalpha and PPARbeta). Observed effects of chronic PPAR stimulation were not related to either AMPK or ERK1/2 activation.
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PMID:Differential effects of chronic, in vivo, PPAR's stimulation on the myocardial subcellular redistribution of FAT/CD36 and FABPpm. 1959 4

Both polyunsaturated fatty acids and AMPK promote energy partitioning away from energy consuming processes, such as fatty acid synthesis, towards energy generating processes, such as beta-oxidation. In this report, we demonstrate that arachidonic acid activates AMPK in primary rat hepatocytes, and that this effect is p38 MAPK-dependent. Activation of AMPK mimics the inhibition by arachidonic acid of the insulin-mediated induction of G6PD. Similar to intracellular signaling by arachidonic acid, AMPK decreases insulin signal transduction, increasing Ser(307) phosphorylation of IRS-1 and a subsequent decrease in AKT phosphorylation. Overexpression of dominant-negative AMPK abolishes the effect of arachidonic acid on G6PD expression. These data suggest a role for AMPK in the inhibition of G6PD by polyunsaturated fatty acids.
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PMID:A role for AMPK in the inhibition of glucose-6-phosphate dehydrogenase by polyunsaturated fatty acids. 1964 64

Cardiomyocyte apoptosis is a component of cardiac remodeling that can contribute to heart failure in obesity. A role for leptin in mediating this process has been suggested and the objective of this work was to investigate the effect of leptin on apoptosis and associated mechanisms in H9c2 cells which were subjected to hypoxia/reoxygenation (HR) to mimic myocardial ischemia/reperfusion. Qualitative immunofluorescent and quantitative laser scanning cytometry approaches demonstrated that exposure of cells to HR increased DNA fragmentation (TUNEL staining) which was attenuated by leptin (6 nM, 1 h) pretreatment. We also found increased annexin-V binding and caspase-3 activity in cells exposed to HR, both of which were attenuated by leptin pretreatment. Leptin reduced HR-induced translocation of the pro-apoptotic protein Bax to the mitochondrial membrane, which provides a mechanism to explain its protective effect. Consequently, leptin attenuated the HR-induced decrease in mitochondrial membrane potential and increase in cytochrome c release from mitochondria. Leptin treatment increased the phosphorylation of p38 MAPK and AMPK and respective inhibitors of these kinases, SB203580 and Compound C, prevented the ability of leptin to decrease HR-induced caspase-3 activity. In conclusion, we establish mechanisms via which leptin exerts anti-apoptotic effects that may be of significance in understanding the development of heart failure in obesity.
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PMID:Leptin attenuates hypoxia/reoxygenation-induced activation of the intrinsic pathway of apoptosis in rat H9c2 cells. 1965 55

The brain controls energy homeostasis and body weight by integrating various metabolic signals. Leptin, an adipose-derived hormone, conveys critical information about peripheral energy storage and availability to the brain. Leptin decreases body weight by both suppressing appetite and promoting energy expenditure. Leptin directly targets hypothalamic neurons, including AgRP and POMC neurons. These leptin-responsive neurons widely connect to other neurons in the brain, forming a sophisticated neurocircuitry that controls energy intake and expenditure. The anorexigenic actions of leptin are mediated by LEPRb, the long form of the leptin receptor, in the hypothalamus. LEPRb activates both JAK2-dependent and -independent pathways, including the STAT3, PI 3-kinase, MAPK, AMPK, and mTOR pathways. These pathways act coordinately to form a network that fully mediates leptin response. LEPRb signaling is regulated by both positive (e.g., SH2B1) and negative (e.g., SOCS3 and PTP1B) regulators and by endoplasmic reticulum stress. Leptin resistance, a primary risk factor for obesity, likely results from impairment in leptin transport, LEPRb signaling, and/or the neurocircuitry of energy balance.
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PMID:Recent advances in understanding leptin signaling and leptin resistance. 1972 19


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