33 research outputs found
The function of embryonic stem cell-expressed Ras (E-Ras), a unique Ras family member, correlates with its additional motifs and its structural properties
E-RAS is a member of the RAS family specifically expressed in embryonic stem cells, gastric tumors, and hepatic stellate cells. Unlike classical RAS isoforms (H-, N-, and K-RAS4B), E-RAS has, in addition to striking and remarkable sequence deviations, an extended 38-amino acid-long unique N-terminal region with still unknown functions. We investigated the molecular mechanism of E-RAS regulation and function with respect to its sequence and structural features. We found that N-terminal extension of E-RAS is important for E-RAS signaling activity. E-RAS protein most remarkably revealed a different mode of effector interaction as compared with H-RAS, which correlates with deviations in the effector-binding site of E-RAS. Of all these residues, tryptophan 79 (arginine 41 in H-RAS), in the interswitch region, modulates the effector selectivity of RAS proteins from H-RAS to E-RAS features
Acceptance and Commitment Therapy and Relational Frame Theory in the Field of Applied Behavior Analysis: The Acceptability and Perspective of the Practicing BCBA
Multiple Locations of Peptides in the Hydrocarbon Core of Gel-Phase Membranes Revealed by Peptide 13
Assessing health-related quality of life in urology â a survey of 4500 German urologists
Randomized Controlled Trial Evaluation of ABA Content on IQ Gains in Children with Autism
Chloride channel accessory 1 integrates chloride channel activity and mTORC1 in agingârelated kidney injury
The mechanism of kidney injury in aging are not well understood. In order to identify hitherto unknown pathways of agingârelated kidney injury, we performed RNAâSeq on kidney extracts of young and aged mice. Expression of chloride (Cl) channel accessory 1 (CLCA1) mRNA and protein was increased in the kidneys of aged mice. Immunostaining showed a marked increase in CLCLA1 expression in the proximal tubules of the kidney from aged mice. Increased kidney CLCA1 gene expression also correlated with aging in marmosets and in a human cohort. In aging mice, increased renal cortical CLCA1 content was associated with hydrogen sulfide (H2S) deficiency, which was ameliorated by administering sodium hydrosulfide (NaHS), a source of H2S. In order to study whether increased CLCA1 expression leads to injury phenotype and the mechanisms involved, stable transfection of proximal tubule epithelial cells overexpressing human CLCA1 (hCLCA1) was performed. Overexpression of hCLCA1 augmented Clâ current via the Ca++âdependent Clâ channel TMEM16A (anoctaminâ1) by patchâclamp studies. hCLCA1 overexpression also increased the expression of fibronectin, a matrix protein, and induced the senescenceâassociated secretory phenotype (SASP). Mechanistic studies underlying these changes showed that hCLCA1 overexpression leads to inhibition of AMPK activity and stimulation of mTORC1 as cellular signaling determinants of injury. Both TMEM16A inhibitor and NaHS reversed these signaling events and prevented changes in fibronectin and SASP. We conclude that CLCA1âTMEM16AâClâ current pathway is a novel mediator of kidney injury in aging that is regulated by endogenous H2S.Chloride channel accessory 1 expression is increased in the tubular epithelial cells of aged kidneys. In vitro experiments show that CLCA1 augments the activity of TMEM16A, a Ca++âdependent Chloride Channel, activates mTORC1, augments the synthesis of matrix proteins, and induces SASP, whcih contribute to aging associated kidney injury.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168458/1/acel13407_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168458/2/acel13407-sup-0001-Supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168458/3/acel13407.pd