Disease relevance of TPM2

• Mutations in the beta-tropomyosin (TPM2) gene--a rare cause of nemaline myopathy [1].
• We excluded two known arthrogryposis loci on chromosome 9p13 (TPM2) and 11p15 (TNNI2, TNNT3) [2].
• Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer [3].
• N-Methyldopamine (epinine), one of the few modifications of the dopamine (DA) molecule that retains agonist activity at the DA1 receptor, was administered orally as the diisobutyric ester, ibopamine (100, 200, and 300 mg), to 15 patients with congestive heart failure [4].
• Forty proteins were identified, of which five [i.e., alpha-amylase; copper zinc superoxide dismutase; protein disulfide isomerase, pancreatic; tropomyosin 2 (TM2); and galectin-1] had been associated previously with pancreatic disease in gene expression studies [5].

High impact information on TPM2

• Similar results were obtained in cells transiently transfected with a plasmid containing a portion of the beta-tropomyosin gene [6].
• The beta tropomyosin synthesized in the intact cells and in the cell-free system can be separated by isoelectric focusing into at least two components [7].
• Administration of the calcineurin inhibitors cyclosporin and FK506 prevented disease in mice that were genetically predisposed to develop HCM as a result of aberrant expression of tropomodulin, myosin light chain-2, or fetal beta-tropomyosin in the heart [8].
• In the rat beta-tropomyosin (beta-TM) gene, exons 6 and 7 are spliced alternatively in a mutually exclusive manner [9].
• Binding of hnRNP H to an exonic splicing silencer is involved in the regulation of alternative splicing of the rat beta-tropomyosin gene [9].

Chemical compound and disease context of TPM2

• Dopexamine is a parenteral agent that selectively activates both DA1 and beta 2 adrenergic receptors and is being evaluated in patients with CHF and in individuals with postoperative left ventricular dysfunction [10].
• DA1-receptor stimulation by fenoldopam in the treatment of postcardiac surgical hypertension [11].

Biological context of TPM2

• Genomic clones isolated with the STS product were in turn used in fluorescence in situ hybridisation to metaphase chromosome spreads to further localise TPM2 to 9p13 [12].
• The STS was used to amplify DNA from somatic cell hybrids to localise TPM2 to human chromosome 9 [12].
• We have described a large Chinese DA family in which different individuals had phenotypes similar to DA1 or DA2B [13].
• We also present evidence to suggest that this cytoskeletal tropomyosin and a human skeletal muscle beta-tropomyosin are derived from a common structural gene by an alternative RNA splicing mechanism [14].
• We found that an excess of SF2/ASF effectively prevents inappropriate exon skipping and also influences the selection of mutually exclusive tissue-specific exons in natural beta-tropomyosin pre-mRNA [15].

Anatomical context of TPM2

• Skeletal muscle expresses three tropomyosin (Tm) isoforms from separate genes: alphaTm(fast)(alphaTm, TPM1), betaTm (TPM2), and alphaTm(slow) (gammaTm, TPM3) [16].
• TGF-beta induction of stress fibers in epithelial cells requires high molecular weight tropomyosins encoded by TPM1 and TPM2 genes [17].
• The rat beta-tropomyosin gene encodes two isoforms, termed skeletal muscle beta-tropomyosin and fibroblast last tropomyosim 1 (TM-1), via an alternative RNA processing mechanism [18].
• During the transition from myoblasts to myotubes, initiation of transcription continues from the internal promoter but also occurs from the distal promoter in order to give rise to the skeletal beta-tropomyosin-specific transcript [19].
• These data indicate that DA-induced lower esophageal sphincter relaxation in vitro is mediated by DA1 receptors [20].

Associations of TPM2 with chemical compounds

• Treatment of these cells with demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) increased mRNA levels of TPM1 with no effect on TPM2 [17].
• It may be caused by mutations in at least five genes: slow alpha-tropomyosin 3 (chromosome 1q22-23), nebulin (chromosome 2q21.1-q22), actin (chromosome 1q42), tropomyosin 2 (chromosome 9p13), and troponin T1 (chromosome 19q13.4) [21].
• DA1 receptor mediates dopamine-induced relaxation of opossum lower esophageal sphincter in vitro [20].
• In addition, agonist responses were studied in the presence of the selective DA2 receptor antagonist domperidone, a mixed DA1/DA2 receptor antagonist metoclopramide, and the selective DA1 receptor antagonists bulbocapnine and SK&F 83566 [20].
• Microinjection of a monoclonal antibody against a 37-kD protein (tropomyosin 2) prevents the formation of new acetylcholine receptor clusters [22].

Physical interactions of TPM2

• Polypyrimidine tract binding protein interacts with sequences involved in alternative splicing of beta-tropomyosin pre-mRNA [23].

Other interactions of TPM2

• A recessive mutation causing nemaline myopathy among the Old Order Amish has recently been identified in the gene for slow skeletal muscle troponin T. As linkage studies had shown that at least one further gene exists for nemaline myopathy, we investigated another tropomyosin gene expressed in skeletal muscle, the beta-tropomyosin 2 gene [1].
• Compared with unsuspended controls, experimental animals had a 0.5- to 0.6-fold decrease in tension during unloading and early reloading, comparable to 0.2- to 0.6-fold decreases in the protein levels of myosin light chain 1 (MLC1), alpha-actin, tropomyosin beta-chain, and troponins T1 and T2 [24].
• Animal cap assays in Xenopus embryos revealed that myogenin, but not the other myogenic regulatory factors, induced expression of embryonic/larval isoforms of the beta-tropomyosin and myosin heavy chain genes [25].
• Of these 8 proteins, 3 had putative isoforms recognized before treatment, and 5 (calreticulin, tropomyosin 1, tropomyosin 2, paramyosin, and triose phosphate isomerase) did not [26].
• alpha- and beta-tropomyosin in typed single fibers of human skeletal muscle [27].

Analytical, diagnostic and therapeutic context of TPM2

• Expression analysis by RT-PCR and by whole mount in situ hybridization demonstrate that Tpm2 is exclusively expressed in striated muscle cells of the medusa [28].
• Linkage mapping in a three-generation family with a distal arthrogryposis (DA) phenotype intermediate between DA2A and DA1 indicated linkage to 11p15.5 but not 9p13 [29].
• Several dehalogenases were closely related to group I and II alpha-halocarboxylic acid dehalogenases, and partial polymerase chain reaction (PCR) products were obtained from isolates DA1, 2, 3 and 4 using degenerate dehalogenase primers [30].
• Using fluorescence in situ hybridization we found subspeckles to be colocalized with transiently expressed beta-tropomyosin RNA transcripts [31].
• We have used human beta-tropomyosin produced in Escherichia coli and deletion mutants obtained by site-directed mutagenesis to analyse the conformational stability of this molecule under various experimental conditions [32].

References