BACKGROUND PINCH is an LIM (double zinc finger domain) protein that functions as an adapter at a key convergence point for integrin and growth factor signal transduction. Because no information is available regarding its expression in vivo in human tissues, this study evaluated the distribution and abundance of PINCH in patients with breast, prostate, lung, colon, and skin carcinomas. METHODS A polyclonal antibody was raised to a purified 6‐histidine PINCH fusion protein and used to evaluate 74 cases comprising 33 breast carcinomas (21 ductal carcinomas, 6 lobular carcinomas, 4 ductal carcinomas in situ, 2 lobular carcinomas in situ), 22 prostate carcinomas, 5 colon carcinomas, 6 lung carcinomas (3 adenocarcinomas and 3 squamous carcinomas), and 8 skin carcinomas (4 basal cell carcinomas and 4 squamous cell carcinomas) by immunoperoxidase histochemistry of formalin‐fixed, paraffin‐embedded tissues. Lysates of frozen tissue from the epithelium of two normal breasts and six breast carcinomas were evaluated by immunoblotting. RESULTS Immunostaining for PINCH was increased in the cytoplasm of fibroblastoid cells in areas of the tumor‐associated stroma in all carcinomatous tissues evaluated. The most intense stromal immunostaining for PINCH was noted at invasive edges, particularly in breast carcinomatous tissue. Immunoblotting of lysates from normal breast and breast carcinomatous tissue confirmed that PINCH protein expression was markedly increased in breast carcinomatous tissues. CONCLUSIONS PINCH is up‐regulated in tumor‐associated stromal cells, particularly at invasive edges, and may be a marker for stroma manifesting the ability to facilitate invasion. Because of this and because PINCH functions as a “molecular switch” in signal transduction, PINCH may be a new target for drug discovery aimed at the tumor‐associated stroma. Cancer 2002;95:1387–95. © 2002 American Cancer Society. DOI 10.1002/cncr.10878
Background-PINCH proteins are 5 LIM domain-only adaptor proteins that function as key components of the integrin signaling pathway and play crucial roles in multiple cellular processes. Two PINCH proteins, PINCH1 and PINCH2, have been described in mammals and share high homology. Both PINCH1 and PINCH2 are ubiquitously expressed in most tissues and organs, including myocardium. Cardiac-specific PINCH1 knockout or global PINCH2 knockout mice exhibit no basal cardiac phenotype, which may reflect a redundant role for these 2 PINCH proteins in myocardium. A potential role for PINCH proteins in myocardium remains unknown. Methods and Results-To define the role of PINCH in myocardium, we generated mice that were doubly homozygous null for PINCH1 and PINCH2 in myocardium. Resulting mutants were viable at birth but developed dilated cardiomyopathy and died of heart failure within 4 weeks. Mutant hearts exhibited disruptions of intercalated disks and costameres accompanied by fibrosis. Furthermore, multiple cell adhesion proteins exhibited reduced expression and were mislocalized. Mutant cardiomyocytes were significantly smaller and irregular in size. In addition, we observed that the absence of either PINCH1 or PINCH2 in myocardium leads to exacerbated cardiac injury and deterioration in cardiac function after myocardial infarction. Conclusions-These results demonstrate essential roles for PINCHs in myocardial growth, maturation, remodeling, and function and highlight the importance of studying the role of PINCHs in human cardiac injury and cardiomyopathy. (Circulation. 2009;120:568-576.)Key Words: cardiomyopathy Ⅲ cell adhesion molecules Ⅲ heart failure Ⅲ pinch protein, mouse Ⅲ remodeling C ells communicate with their microenvironment and neighbors by several specialized cell membrane-associated structures. In myocardium, these include costameres and intercalated disks, which provide mechanical and electric coupling between myocytes and enable myocardium to function as a syncytium. Dysfunction of cell adhesions in both animal models and human diseases is implicated in the pathogenesis of cardiomyopathy, heart failure, and injury repair. [1][2][3][4][5] Clinical Perspective on p 576Myocardial cell-matrix adhesion at the costamere is mediated by integrin-1 receptor and its associated complex and plays vital roles in morphogenesis and tissue integrity by regulating multiple cellular processes such as cell adhesion, proliferation, differentiation, and survival. 6 -10 Engagement of integrin with extracellular matrix leads to recruitment and formation of a cytoplasmic focal adhesion complex composed of integrin-linked kinase (ILK), Parvin, and PINCH, which links integrins to the actin cytoskeleton and other intracellular pathways. 6 In contrast to Drosophila and Caenorhabditis elegans, which have only 1 PINCH protein, 2 PINCH proteins, PINCH1 and PINCH2, have been described in mammals and share high sequence and structural similarity. 11 PINCH1 is expressed in the blastocyst, whereas PINCH2 expression starts on embryonic d...
The current studies were undertaken to explore the relationship between enhanced sympathetic nervous activity and lymphocyte subset distribution in three settings: congestive heart failure, dynamic exercise, and fl-adrenergic agonist treatment.We compared the number and subset distribution of circulating lymphocytes in 36 patients with congestive heart failure and 31 age-matched control subjects. The number of circulating lymphocytes was lower in heart failure than in control. This was due to a reduction in Tsuppressor/cytotoxic and natural killer cells without significant alteration of Thelper cells. The extent of the alteration was similar in patients with idiopathic and ischemic heart failure, but the reduction was more pronounced in patients with New York Heart Association class III-IV than in class 1-11. The plasma catecholamine elevation in heart failure was also independent of etiology but more pronounced in the more severely ill patients. We also assessed lymphocyte subsets after acute stimulation of sympathetic activity by dynamic exercise and after treatment with the ,8-adrenergic agonist terbutaline. Dynamic exercise until exhaustion increased the number of circulating lymphocytes in healthy controls and heart failure patients in a subset-selective manner. By contrast, a 7-d treatment with terbutaline caused a reduction in the circulating number of lymphocytes in some subsets that was identical to that seen in heart failure patients. We conclude that prolonged sympathetic activity reduces the number of circulating lymphocytes by a fi-adrenergic mechanism. Such alterations might be involved in the pathophysiology of heart failure and other disease states involving increased activity of the sympathetic nervous system. (J. Clin. Invest. 1990. 85:462-467.) beta receptors -lymphocytes -heart failuresympathetic nervous system
Particularly interesting new cysteine-histidine-rich protein (PINCH), a LIM domain adapter protein that functions in the integrin and growth factor signal transduction pathway, is upregulated in stroma associated with many common cancers. The finding suggested that PINCH may be involved in promoting tumor-stromal interactions that support tumor progression, and, if so, tumors with abundant PINCH stromal staining may have a worse prognosis. To test this hypothesis, 174 primary colorectal adenocarcinomas with 39 distant normal mucosa samples and 26 metastases in the lymph nodes were studied by immunohistochemistry, and 7 additional colon tumors were studied by Western blot analysis and immunofluorescence. The abundance of PINCH protein in stroma increased from normal mucosa to primary tumor to metastasis (P <.05), and was more intense at the invasive margin than it was in the intratumoral stroma. Strong stromal immunostaining for PINCH was shown to predict a worse outcome (rate ratio 2.1, 95% CI 1.16-3.37, P=.01), independent of Dukes stage, growth pattern, and tumor differentiation. PINCH was detected in fibroblasts, myofibroblasts, and a proportion of endothelial cells of the tumor vasculature, supporting the involvement of PINCH in promoting tumor-stromal interactions that support tumor progression. Interestingly, stromal staining for PINCH was an independent prognostic indicator in colorectal cancer.
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