Biomedical subjects

L Baki

Publications and source records attributed to L Baki.

4 recordsLinked to original sources

PubMed2001

Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex.

Here we show that presenilin-1 (PS1), a protein involved in Alzheimer's disease, binds directly to epithelial cadherin (E-cadherin). This binding is mediated by the large cytoplasmic loop of PS1 and requires the membrane-proximal cytoplasmic sequence 604-615 of mature E-cadherin. This sequence is also required for E-cadherin binding of protein p120, a known regulator of cadherin-mediated cell adhesion. Using wild-type and PS1 knockout cells, we found that increasing PS1 levels suppresses p120/E-cadherin binding, and increasing p120 levels suppresses PS1/E-cadherin binding. Thus PS1 and p120 bind to and mutually compete for cellular E-cadherin. Furthermore, PS1 stimulates E-cadherin binding to beta- and gamma-catenin, promotes cytoskeletal association of the cadherin/catenin complexes, and increases Ca(2+)-dependent cell-cell aggregation. Remarkably, PS1 familial Alzheimer disease mutant DeltaE9 increased neither the levels of cadherin/catenin complexes nor cell aggregation, suggesting that this familial Alzheimer disease mutation interferes with cadherin-based cell-cell adhesion. These data identify PS1 as an E-cadherin-binding protein and a regulator of E-cadherin function in vivo.

Animals↗

PubMed1996

Regulation of tyrosine aminotransferase gene expression by glucocorticoids in quiescent and regenerating liver.

Following 70% hepatectomy, the induction of tyrosine amino-transferase mRNA by glucocorticoids was marginal at 1.5 h, significantly impaired between 3 and 8 h and, at 16 h post-hepatectomy, reached a value approx. 5-fold the basal level, similar to the level observed in quiescent liver. The fold induction of the mRNA was accounted for by a similar fold activation of transcription of the gene by glucocorticoids in regenerating but not in quiescent liver; in the latter, activation of transcription was marginal in spite of glucocorticoid-induced hypersensitivity to cleavage by DNase I at the glucocorticoid-dependent enhancer of the gene. The possibility that in quiescent liver glucocorticoids act at a transcriptional step beyond initiation, increasing the rate of elongation or overcoming a blockage in elongation, was excluded. However, a similar fold induction was determined for total and nuclear tyrosine aminotransferase mRNA in the presence of glucocorticoids, suggesting that in quiescent liver glucocorticoids promote efficient maturation of the tyrosine aminotransferase primary transcript. Thus a glucocorticoid-induced nuclear post-transcriptional up-regulation apparently compensates for impaired activation of transcription of the tyrosine aminotransferase gene by glucocorticoids in quiescent liver.

Animals↗

PubMed1994

The efficiency of nuclear processing of the tyrosine aminotransferase mRNA transcript increases after partial hepatectomy.

Following a two-thirds partial hepatectomy, an approximately fivefold increase in the levels of nuclear and total mRNA for tyrosine aminotransferase was observed at 1 h and 1.5 h, respectively, and a return to the levels of the quiescent state, i.e. the levels found in non-operated livers from adrenalectomized rats, was established 16 h post-hepatectomy. The increase in mRNA levels was not accounted for by a comparable change in the rate of transcription of the gene which, at 0.5 h post-hepatectomy, reached a maximum value that amounted to only 1.4-fold the value for quiescent liver. Subsequent changes in the transcription rate largely accounted for the changes in mRNA levels observed later on. Although tyrosine aminotransferase mRNA levels were equal in quiescent and 16-h-regenerating liver, the rate of transcription of the gene in quiescent liver was threefold higher than the rate in 16-h-regenerating liver. The maintenance of a higher rate of gene transcription in quiescent liver, as compared to regenerating liver, was shown to depend on ongoing protein synthesis. The possibility that the high rate of gene transcription was due to blockage or pausing during transcript elongation in quiescent liver was excluded. The inference is that the pronounced increase in tyrosine aminotransferase mRNA levels within 1 h of partial hepatectomy is largely due to a rapid increase in the efficiency of nuclear processing of the primary transcript.

Animals↗

PubMed1988

Glucocorticoid receptor structure as probed by endogenous proteases.

Transformation of the glucocorticoid-receptor complex by heating the cytosol in the presence of calcium is accompanied by formation of a series of truncated complexes, of which DI and DIIc are the major members. Formation of DIIc (but not of DI) is inhibited by leupeptin, and the intact transformed complex DIIa appears instead. Estimation of the molecular weights and Stokes' radii of all major complexes revealed that forms DI and DIIc have the same Mr, 48 kDa, but differ in shape, and appear to be digestion products generated by cleavage at the same site. Proteolysis of glucocorticoid receptor, covalently labelled with [3H]dexamethasone mesylate in rat thymus and brain cytosol, corroborated these findings and further implied that DI is the product of digestion of the non-transformed form of the receptor. Covalently labelled receptor fragments, related to the products formed when cytosol is heated, are detected in the nuclei of thymocytes, implying that the same proteolytic cleavages sites are involved in receptor turnover. Cleavage sites in the non-transformed covalently labelled receptor were identified in the "stepladder" of fragments of Mr, 85, 65, 49, 35, 27-30 kDa, generated in the absence of calcium, with an additional 78 kDa fragment in its presence. In the transformed conformation, two of the cleavage sites giving rise to the 65 and 35 kDa fragments, appear to be protected. It is speculated that the change in the proteolytic susceptibility of the cleavage site for the 35 kDa fragment relates to the "unmasking" of enhancer-activating and/or DNA-binding receptor functions previously postulated.

Adrenalectomy↗