Abstract
Cardiovascular disease and cancer are increased in Type 2 diabetes. TPM1 and TPM4 genes encode proteins associated with cardiovascular and neoplastic disease. High (HMW) and low (LMW) molecular weight isoforms from TPM1 and TPM4 are altered in several cancer cells and the 3'UTR of TPM1 mRNA is tumour suppressive. Leukocytes influence cardiovascular and neoplastic disease by immunosurveillance for cancer and by chronic inflammation in Type 2 diabetes and cardiovascular disease. The aim was to determine changes in expression of isoforms from TPM1 and TPM4 genes in leukocytes from Type 2 diabetic patients and to use the leukocyte cell line THP1 to identify possible mediators of changes in the patients. Gene expression was determined by RT-qPCR. In diabetes, expression of HMW isoforms from TPM1 were markedly decreased (0.55 v 1.00; p = 0.019) but HMW isoforms from TPM4 were not significantly different (0.76 v 1.00; p = 0.205). Within individual variance in expression of HMW isoforms was very high. The change in expression in HMW isoforms from TPM1 and TPM4 was replicated in THP1 cells treated with 1 ng/ml TNFα (0.10 and 0.12 v 1.00 respectively) or 10 ng/ml IL-1α (0.17 and 0.14 v 1.00 respectively). Increased insulin or glucose concentrations had no substantial effects on TPM1 or TPM4 expression. Decreased TPM1 mRNA resulted in decreases in HMW protein levels. Expression of HMW isoforms from TPM1 is decreased in Type 2 diabetes. This is probably due to increased levels of inflammatory cytokines TNFα and IL-1α in Type 2 diabetes. Lower levels of TPM1 mRNA reduce tumour suppression and could contribute to increased cancer risk in Type 2 diabetes. Decreased HMW tropomyosin isoforms are associated with cancer. Decreased HMW isoforms give rise to cells that are more plastic, motile, invasive and prone to dedifferentiation resulting in leukocytes that are more invasive but less functionally effective.
Highlights
Tropomyosins are a group of proteins that are a major component of muscle fibres in all types of muscle cell and are a critical component of actin stress fibres in the cytoskeleton of all cells
We have investigated the expression of tropomyosin isoforms from TPM1 and TPM4 in patients with Type 2 diabetes
The results of this study strongly indicate that there are decreased levels of expression of high molecular weight (HMW) isoforms from TPM1 and TPM4 in leukocytes from Type 2 diabetic patients and that these are due to elevated levels of inflammatory cytokines in those patients
Summary
Tropomyosins are a group of proteins that are a major component of muscle fibres in all types of muscle cell and are a critical component of actin stress fibres in the cytoskeleton of all cells To fulfil this range of functions tropomyosins are encoded by 4 genes, TPM1, 2, 3 and 4, each of which give rise to multiple protein isoforms by variable exon splicing. Actin stress fibres of the cytoskeleton, in which tropomyosin isoforms have a critical function in structure and remodelling [2], determine many aspects of cell development and behaviour They are important in regulating motility and invasion by leukocytes [3] and in many other aspects of cell membrane function such as recognition by membrane receptors and subsequent intracellular signalling [4]. They are critical in the development of diseased cells such as in dedifferentiation that is characteristic of neoplastic cells in cancer development [5] and in smooth muscle cells in atheromatous lesions [6]
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