Disease relevance of Tpm1

• Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction [1].
• We previously developed two transgenic mouse models that carry FHC-associated mutations in alpha-tropomyosin (TM): FHC alpha-TM175 mice show patchy areas of mild ventricular disorganization and limited hypertrophy, whereas FHC alpha-TM180 mice exhibit severe hypertrophy and fibrosis and die within 6 mo [2].
• Skeletal muscle function was measured in anaesthetised transgenic mice having a mutation in the TPM3 gene (slow alpha-tropomyosin), a similar mutation as found in some patients with nemaline myopathy, and was compared with control muscles [3].

High impact information on Tpm1

• Specific antibodies have been used to show that in adult skeletal muscle the slow and fast forms of the components of the troponin complex are located in type I and type II fibres respectively. alpha-Tropomyosin is restricted to type II cells [4].
• The PTB interacting protein raver1 regulates alpha-tropomyosin alternative splicing [5].
• Regulated switching of the mutually exclusive exons 2 and 3 of alpha-tropomyosin (TM) involves repression of exon 3 in smooth muscle cells [5].
• In the present study, we find that during differentiation of BC3H1 cells, induced by mitogen withdrawal, induction of the JCC and DHP receptor mRNAs is temporally similar to that of the skeletal muscle contractile protein genes alpha-tropomyosin and alpha-actin [6].
• During rapid growth, subconfluent BC3H1 cells express the nonmuscle isoform of alpha-tropomyosin (alpha-Tm) and the nonsarcomeric isoforms of myosin heavy and light chains (MHCs and MLCs, respectively), but do not express troponin T(TnT) [7].

Biological context of Tpm1

• S1 nuclease mapping and Western blot analyses demonstrate that increased expression of the alpha-TM 175 transgene in different lines causes a concomitant decrease in levels of endogenous alpha-TM mRNA and protein expression [1].
• Cardiac gross morphology, histology, and function (assessed by working heart preparations) of heterozygous alpha-tropomyosin knockout and wild-type mice were indistinguishable [8].
• These findings imply that in heterozygotes there is a regulatory mechanism that maintains the level of myofibrillar tropomyosin despite the reduction in alpha-tropomyosin mRNA [8].
• These results demonstrate the importance of alpha-tropomyosin to the phenotype of this mutation and to normal myofibril formation [9].
• This study developed transgenic mouse lines that encode an FHC mutation in alpha-tropomyosin; this mutation is an amino acid substitution at codon 180 (Glu180Gly) which occurs in a troponin T binding region [10].

Anatomical context of Tpm1

• Charged residue alterations in the inner-core domain and carboxy-terminus of alpha-tropomyosin differentially affect mouse cardiac muscle contractility [11].
• Myofilaments that contain alpha-TM 175 demonstrate an increased activation of the thin filament through enhanced Ca2+ sensitivity of steady-state force [1].
• These results suggest that TM2 is expressed from the same gene that encodes the smooth muscle alpha-TM, the skeletal muscle alpha-TM, and TM3 via an alternative RNA-splicing mechanism [12].
• Surprisingly, this reduction in alpha-TM mRNA levels in heterozygous mice is not reflected at the protein level, where normal amounts of striated muscle alpha-TM protein are produced and integrated in the myofibril [13].
• We created a mouse that lacks a functional alpha-tropomyosin gene using gene targeting in embryonic stem cells and blastocyst-mediated transgenesis [8].

Associations of Tpm1 with chemical compounds

• Two important charge differences in beta-TM compared to alpha-TM are the exchange of serine and histidine at positions 229 and 276 with glutamic acid and asparagine, respectively, imparting a more negative charge to beta-TM relative to alpha-TM [14].
• The third mRNA, encoding alpha-tropomyosin, was specifically up-regulated by ethanol [15].

Regulatory relationships of Tpm1

• When mouse alpha-tropomyosin cDNA under the control of a cardiac-specific alpha-myosin heavy chain promoter was transfected into the mutant hearts, tropomyosin expression was enhanced resulting in the formation of well-organized sarcomeric myofibrils [9].

Other interactions of Tpm1

• Our earlier results succinctly demonstrate that overexpression of beta-tropomyosin in the hearts of transgenic mice decreases endogeneous alpha-tropomyosin levels while altering diastolic function of the myocardium [16].
• Furthermore, the 3' untranslated region riboregulator of the alpha-tropomyosin gene is not needed for the inhibition of ras-induced growth [17].
• Surprisingly, other TMs, such as the striated muscle beta-TM and smooth muscle alpha-TM, are expressed constitutively [18].
• Homozygous alpha-TM null mice are embryonic lethal, dying between 8 and 11.5 days post coitum [13].
• Northern blot analysis showed that cis-OH-Pro- and EDHB-treated C2C12 muscle cells did not express the myogenic regulatory genes, MyoD1 and myogenin, but continued to express non-muscle isoforms of actin (beta and gamma) and alpha-tropomyosin [19].

Analytical, diagnostic and therapeutic context of Tpm1

• Alpha-Tropomyosin from rat cardiac muscle was shown by two-dimensional gel electrophoresis to become phosphorylated when tissue slices were incubated in Eagle's medium supplemented with 32Pi [20].
• Previous studies have introduced wild-type mouse alpha-tropomyosin into mutant hearts in organ culture with subsequent for-mation of organized myofibrils [21].

References