Myosin light chain kinase knockout.
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Animals↗
Biomedical subjects
M Majesky
Publications and source records attributed to M Majesky.
Activation of the cardiac alpha-actin promoter depends upon serum response factor, Tinman homologue, Nkx-2.5, and intact serum response elements.
A murine cardiac specific homeoboxgene, Nkx-2.5/CSX, a potential Drosophila tinman homologue, may have a fundamental role in cardiac myocyte differentiation. DNA binding targets for Nkx-2.5 were recently shown to represent novel homeodomain binding sequences, some of which resembled serum response elements (SREs); [Chen CY, Schwartz RJ (1995): J Biol Chem 270: 15628-15633]. In this study, Nkx-2.5 facilitated serum response factor (SRF) DNA-binding activity to the multiple SREs found on the cardiac alpha-actin promoter and together stimulated cardiac alpha-actin promoter dependent transcription in 10T1/2 fibroblasts. Analysis of cardiac alpha-actin promoter mutants demonstrated the importance of the multiple upstream SREs and an obligatory requirement for an intact proximal SRE1, for providing high levels of activity in the presence of Nkx-2.5 and SRF coexpression. Transfection assays with mutant SRF species indicated that the C-terminal activation domain and DNA-binding MADS box were necessary for transcriptional activity in the presence of Nkx-2.5. Expression of Nkx-2.5 mutants also demonstrated that the homeodomain alone was insufficient for directing promoter activity in the presence of SRF. The central role of SRF in regulating striated alpha-actin gene activity also was revealed by its embryonic expression restricted primarily to myocardium of the developing heart and the myotomal portion of somites. Thus the function of the cardiac actin promoter SREs appeared to provide binding sites for SRF and Nkx-2.5 to interact and elicit striated muscle specific transcription that was independent of the MyoD family.
Actins↗
Tenascin synthesis, deposition, and isoforms in monocrotaline-induced pulmonary hypertensive rat lungs.
Monocrotaline (MCT)-induced pulmonary hypertension is characterized by alterations in vascular extracellular matrix and neomuscularization of small blood vessels. Tenascin (TN) is a matrix glycoprotein which modulates cellular attachment, proliferation, and migration. The present study used immunohistochemistry and Northern analyses to examine the hypothesis that treatment of rats with the potent pneumotoxin MCT induces temporal alterations in TN synthesis/deposition in the affected lungs. MCT produced progressive pathological alterations in the cardiopulmonary system, including increased dry lung weight, right ventricular hypertrophy, and pulmonary hypertension by days 7, 14, and 21, respectively. TN positive foci were first observed in the parenchyma surrounding small muscularized pulmonary arteries in MCT-treated rats at day 4; these foci became both more pronounced and frequent as the disease progressed. TN was also observed in the media of the intrapulmonary artery at day 21. Northern analysis demonstrated increases in TN transcripts in MCT-treated rats as early as day 1. Furthermore, a unique transcript, apparently lacking some fibronectin type III-like units, was observed in mRNA extracted from these rats. These data demonstrate alterations in TN synthetic capacity and focal increases in TN deposition in lungs from MCT-treated rats and suggest that TN may be associated with the pathogenesis of pulmonary hypertension.
Animals↗
Tenascin expression in nephrogenesis and in normal or pathologic glomerulus morphologic features and functional implications.
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Animals↗
Tenascin is an important component of the glomerular extracellular matrix in normal and pathologic conditions.
Tenascin (TN), a large oligomeric glycoprotein, is a recently described component of the extracellular matrix (ECM). Previous reports focusing largely on the role of TN in nephrogenesis have documented the strong expression of TN in embryonic kidney tissue and implied an important role for TN in nephrogenesis. However, the expression of TN in normal and pathologic kidneys in adults has not been systematically evaluated. In this study immunohistochemical staining for TN was applied to 184 renal specimens diagnosed as: normal kidney (23 cases); minimal change disease and its variants (8); mesangial proliferative glomerulonephritis (GN) including IgA nephropathy and mesangial proliferative lupus nephritis (9); endocapillary proliferative GN including membranoproliferative GN, lupus nephritis, and post-infectious GN (25); crescentic GN (11); membranous GN (19); focal segmental sclerosis (15); thrombotic microangiopathy (8); amyloidosis (5); diabetic nephropathy (9); primary tubulointerstitial nephritis (14); transplant rejection (14); and ischemia (24). It was found that: (a) there was unequivocal global diffuse staining limited to the mesangium in normal kidney; (b) regardless of the etiologies and the morphologic types of glomerular disease, whenever there was expansion of the ECM, whether in the mesangial, endocapillary, or extracapillary spaces, there was a concomitant and proportional in situ increase in the TN staining; (c) globally sclerotic glomeruli, regardless of causes, showed diffuse, strong staining, especially in the subcapsular fibrous deposition seen in ischemic sclerosis; (d) non-sclerotic glomeruli showing early ischemic change uniformly displayed a marked decrease or complete loss of staining; (e) in cases of thrombotic microangiopathy, there was segmental or global staining of the capillary wall, probably corresponding to the enlarged lamina rara interna; (f) all nodular lesions in diabetic glomerulosclerosis showed strong staining, but in several of them this staining was much more pronounced in the periphery than in the center of the lesion. Our study proves that TN is probably a component of the normal mesangial matrix, that TN is an ubiquitous component of the expanded glomerular ECM in pathologic conditions regardless of morphologic subtypes, and that further studies on the cell types and mechanisms responsible for TN synthesis may provide a new venue for the understanding of the process of glomerular sclerosis.
Absorption↗
Molecular cloning and characterization of 2B7, a rat mRNA which distinguishes smooth muscle cell phenotypes in vitro and is identical to osteopontin (secreted phosphoprotein I, 2aR).
We have identified a rat smooth muscle cell mRNA, 2B7, which distinguishes smooth muscle cell phenotypes in vitro. Sequence and tissue distribution data strongly suggest this mRNA to be identical to osteopontin (secreted phosphoprotein I, 2aR). In vivo, 2B7 mRNA is expressed in normal rat aorta and carotid arteries at levels 50-60-fold greater than heart, and about 3-4 times the levels found in adult rat kidney on a per micrograms of total RNA basis. Of the other smooth muscle sources surveyed, significant levels of 2B7 mRNA were detectable in total RNA prepared from rat uterus and stomach, but not intestine. 2B7 mRNA levels in both carotid and aortic artery increase with age, and are elevated approximately 5-fold in the carotid artery 48 h after balloon angioplasty. The presence of osteopontin (secreted phosphoprotein I, 2aR) in the normal artery wall and its increased expression after injury suggests a previously unappreciated role for this molecule in the vascular system.
Amino Acid Sequence↗