Cells continually assess their energy and nutrient state to maintain growth and survival and engage necessary homeostatic mechanisms. Cell-autonomous responses to the fed state require the ...surveillance of the availability of amino acids and other nutrients. The mammalian target of rapamycin complex 1 (mTORC1) integrates information on nutrient and amino acid availability to support protein synthesis and cell growth. We identify the G protein-coupled receptor (GPCR) T1R1/T1R3 as a direct sensor of the fed state and amino acid availability. Knocking down this receptor, which is found in most tissues, reduces the ability of amino acids to signal to mTORC1. Interfering with this receptor alters localization of mTORC1, downregulates expression of pathway inhibitors, upregulates key amino acid transporters, blocks translation initiation, and induces autophagy. These findings reveal a mechanism for communicating amino acid availability through a GPCR to mTORC1 in mammals.
► The T1R1/T1R3 GPCR senses extracellular amino acids promoting mTORC1 activation ► T1R1/T1R3 is required for proper localization of mTOR to the lysosomal compartment ► Silencing T1R1/T1R3 induces changes characteristic of a starvation response ► Small molecule inhibitors of T1R1/T1R3 acutely block mTORC1 activity
The roles of MAPKs in disease Lawrence, Michael C; Jivan, Arif; Shao, Chunli ...
Cell research,
04/2008, Letnik:
18, Številka:
4
Journal Article
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MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs ...have now been identified in diseases ranging from cancer to inflammatory disease to obesity and diabetes. In many cell types, the MAPKs ERK1/2 are linked to cell proliferation. ERK1/2 are thought to play a role in some cancers, because mutations in Ras and B-Raf, which can activate the ERK1/2 cascade, are found in many human tumors. Abnormal ERK1/2 signaling has also been found in polycystic kidney disease, and serious developmental disorders such as cardio-facio-cutaneous syndrome arise from mutations in components of the ERK1/2 cascade. ERK1/2 are essential in well-differentiated cells and have been linked to long-term potentiation in neurons and in maintenance of epithelial polarity. Additionally, ERK1/2 are important for insulin gene transcription in pancreatic beta cells, which produce insulin in response to increases in circulating glucose to permit efficient glucose utilization and storage in the organism. Nutrients and hormones that induce or repress insulin secretion activate and/or inhibit ERK1/2 in a manner that reflects the secretory demand on beta cells. Disturbances in this and other regulatory pathways may result in the contribution of ERK1/2 to the etiology of certain human disorders.
Steroid receptors bind as dimers to a degenerate set of response elements containing inverted repeats of a hexameric half-site separated by 3 bp of spacer (IR3). Naturally occurring selective ...androgen response elements have recently been identified that resemble direct repeats of the hexameric half-site (ADR3). The 3D crystal structure of the androgen receptor (AR) DNA-binding domain bound to a selective ADR3 reveals an unexpected head-to-head arrangement of the two protomers rather than the expected head-to-tail arrangement seen in nuclear receptors bound to response elements of similar geometry. Compared with the glucocorticoid receptor, the DNA-binding domain dimer interface of the AR has additional interactions that stabilize the AR dimer and increase the affinity for nonconsensus response elements. This increased interfacial stability compared with the other steroid receptors may account for the selective binding of AR to ADR3 response elements.
Background The classic cut and sew maze is thought to reduce stroke, in part because of left atrial appendage (LAA) elimination. Multiple LAA elimination techniques have evolved with the introduction ...of new surgical treatment options for atrial fibrillation (AF), but the impact on stroke remains unknown. We studied the rate of late neurologic event (LNE) in the era of contemporary AF surgery. Methods From April 21, 2004, to June 30, 2011, 773 patients underwent surgery for AF. In 131 patients, the LAA was excised. In 579, alternative elimination techniques were used (97 external ligation, 313 internal ligation, 126 stapled excision, 23 stapled excision plus internal ligation, 5 internal plus external ligations, and 15 that did not fit into any category); 63 LAAs were left intact and excluded from analyses. Complete follow-up was obtained by medical record review and phone call. Median survival follow-up was 3.3 years (first and third quartiles, 1.6 and 5.0). An LNE was defined as either a documented stroke or transient ischemic attack 30 or more days after surgery. Baseline characteristics and outcomes between LAA techniques were compared using χ2 , Fisher's exact tests, and Student's t tests. Results There were 25 LNEs (3.5%) overall; the median occurrence time was 3.6 years (first and third quartiles, 1.9 and 5.4) after surgery. There were 17 strokes and 8 transient ischemic attacks. Of 45 demographic and surgical variables, only age, aortic valve surgery, and perioperative neurologic event (<30 days after cardiac surgery) independently predicted LNE ( p = 0.003, 0.021, and 0.010, respectively). Late neurologic events occurred with an annual rate of 1.13% in patients with alternative elimination techniques, and 0.20% in patients with excised LAA ( p = 0.001). Patients in AF at any time were more likely to have LNE, but this was not an independent predictor. Conclusions After surgery for AF ablation, there is ongoing low risk of LNE even when the LAA is surgically excised. Further investigation should be pursued to clarify whether a difference exists with alternative elimination techniques and in patients in whom AF is successfully eliminated.
Initially identified in Chlamydomonas, RSP3 (radial spoke protein 3) is 1 of more than 20 identified radial spoke structural components of motile cilia and is required for axonemal sliding and ...flagellar motility. The mammalian orthologs for this and other radial spoke proteins, however, remain to be characterized. We found mammalian RSP3 to bind to the MAPK ERK2 through a yeast two-hybrid screen designed to identify interacting proteins that have a higher affinity for the phosphorylated, active form of the protein kinase. Consistent with the screening result, the human homolog, RSPH3, interacts with and is a substrate for ERK1/2. Moreover, RSPH3 is a protein kinase A-anchoring protein (AKAP) that scaffolds the cAMP-dependent protein kinase holoenzyme. The binding of RSPH3 to the regulatory subunits of cAMP-dependent protein kinase, RIIα and RIIβ, is regulated by ERK1/2 activity and phosphorylation. Here we describe an ERK1/2-interacting AKAP and suggest a mechanism by which cAMP-dependent protein kinase-AKAP binding can be modulated by the activity of other enzymes.
We report a case of coronary perforation during high-risk percutaneous coronary intervention with Impella (Abiomed, Danvers, Massachusetts) support that resulted in cessation of pulsatile arterial ...flow. Maintenance of systemic perfusion due to antecedent placement of Impella 2.5 allowed for successful treatment with pericardiocentesis and covered stent placement, early discharge, and complication-free follow-up. (Level of Difficulty: Intermediate.)
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We report a case of coronary perforation during high-risk percutaneous coronary intervention with Impella (Abiomed, Danvers, Massachusetts) support…
Lipid treatment guidelines have continued to evolve as new evidence emerges. We sought to review similarities and differences of 5 lipid treatment guidelines from the American College of ...Cardiology/American Heart Association, Canadian Cardiovascular Society, European Society for Cardiology/European Atherosclerosis Society, U.S. Preventive Services Task Force, and U.S. Veterans Affairs/Department of Defense. All guidelines utilize rigorous evidentiary review, highlight statin therapy for primary and secondary prevention of atherosclerotic cardiovascular disease, and emphasize a clinician-patient risk discussion. However, there are differences in statin intensities, use of risk estimators, treatment of specific patient subgroups, and consideration of safety concerns. Clinicians should understand these similarities and differences in current and future guideline recommendations when considering if and how to treat their patients with statin therapy.
Lipid treatment guidelines have continued to evolve as new evidence emerges. We sought to review similarities and differences of 5 lipid treatment guidelines from the American College of ...Cardiology/American Heart Association, Canadian Cardiovascular Society, European Society for Cardiology/European Atherosclerosis Society, U.S. Preventive Services Task Force, and U.S. Veterans Affairs/Department of Defense. All guidelines utilize rigorous evidentiary review, highlight statin therapy for primary and secondary prevention of atherosclerotic cardiovascular disease, and emphasize a clinician-patient risk discussion. However, there are differences in statin intensities, use of risk estimators, treatment of specific patient subgroups, and consideration of safety concerns. Clinicians should understand these similarities and differences in current and future guideline recommendations when considering if and how to treat their patients with statin therapy.
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