Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.

Background: Tropomyosin (TM), an essential actin-binding protein, is central to the control of calcium-regulated striated muscle contraction. Although TPM1alpha (also called alpha-TM) is the predominant TM isoform in human hearts, the precise TM isoform composition remains unclear.

Methods And Results: In this study, we quantified for the first time the levels of striated muscle TM isoforms in human heart, including a novel isoform called TPM1kappa.

An internal domain of beta-tropomyosin increases myofilament Ca(2+) sensitivity.

Tropomyosin (TM) is involved in Ca(2+)-mediated muscle contraction and relaxation in the heart. Striated muscle alpha-TM is the major isoform expressed in the heart. The expression of striated muscle beta-TM in the murine myocardium results in a decreased rate of relaxation and increased myofilament Ca(2+) sensitivity.

Atonal homolog 1 is a tumor suppressor gene.

Colon cancer accounts for more than 10% of all cancer deaths annually. Our genetic evidence from Drosophila and previous in vitro studies of mammalian Atonal homolog 1 (Atoh1, also called Math1 or Hath1) suggest an anti-oncogenic function for the Atonal group of proneural basic helix-loop-helix transcription factors. We asked whether mouse Atoh1 and human ATOH1 act as tumor suppressor genes in vivo.

Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity.

Mutations in striated muscle alpha-tropomyosin (alpha-TM), an essential thin filament protein, cause both dilated cardiomyopathy (DCM) and familial hypertrophic cardiomyopathy. Two distinct point mutations within alpha-tropomyosin are associated with the development of DCM in humans: Glu40Lys and Glu54Lys. To investigate the functional consequences of alpha-TM mutations associated with DCM, we generated transgenic mice that express mutant alpha-TM (Glu54Lys) in the adult heart.

Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis.

Familial hypertrophic cardiomyopathy (FHC) is a disease caused by mutations in contractile proteins of the sarcomere. Our laboratory developed a mouse model of FHC with a mutation in the thin filament protein alpha-tropomyosin (TM) at amino acid 180 (Glu180Gly). The hearts of these mice exhibit dramatic systolic and diastolic dysfunction, and their myofilaments demonstrate increased calcium sensitivity.

Short-form Ron receptor is required for normal IFN-gamma production in concanavalin A-induced acute liver injury.

Abrogation of Ron receptor tyrosine kinase function results in defects in macrophage activation and dysregulated acute inflammatory responses in vivo. Several naturally occurring constitutively active alternative forms of Ron have been identified, including from primary human tumors and tumor cell lines. One of these alternative forms, short-form (SF) Ron, is generated from an alternative start site in intron 10 of the Ron gene that eliminates most of the extracellular portion of the receptor and is overexpressed in several human cancers.

Physiological significance of troponin T binding domains in striated muscle tropomyosin.

Striated muscle tropomyosin (TM) plays an essential role in sarcomeric contraction and relaxation through its regulated movement on the thin filament. Previous work in our laboratory established that alpha- and beta-TM isoforms elicit physiological differences in sarcomeric performance. To address the significance of isoform-specific troponin T binding regions in TM, in this present work we replaced alpha-TM amino acids 175-190 and 258-284 with the beta-TM regions and expressed this chimeric protein in the hearts of transgenic mice.

A mouse model of familial hypertrophic cardiomyopathy caused by a alpha-tropomyosin mutation.

Familial hypertrophic cardiomyopathy, a disease caused by mutations in cardiac contractile proteins, is characterized by left and/or right ventricular hypertrophy, myocyte disarray, fibrosis, and cardiac arrhythmias that may lead to premature sudden death. Five distinct point mutations within alpha-tropomyosin are associated with the development of familial hypertrophic cardiomyopathy. Two of these mutations are found within a troponin T binding site, located at amino acids 175 and 180.

Functional importance of the carboxyl-terminal region of striated muscle tropomyosin.

Striated muscle tropomyosin (TM) interacts with actin and the troponin complex to regulate calcium-mediated muscle contraction. Previous work by our laboratory established that alpha- and beta-TM isoforms elicit physiological differences in sarcomeric performance. Heart myofilaments containing beta-TM exhibit an increased sensitivity to calcium that is associated with a decrease in the rate of relaxation and a prolonged time of relaxation.

Tropomyosin 3 expression leads to hypercontractility and attenuates myofilament length-dependent Ca(2+) activation.

Tropomyosin (TM), an integral component of the thin filament, is encoded by three striated muscle isoforms: alpha-TM, beta-TM, and TPM 3. Although the alpha-TM and beta-TM isoforms are well characterized, less is known about the function of the TPM 3 isoform, which is predominantly found in the slow-twitch musculature of mammals. To determine its functional significance, we ectopically expressed this isoform in the hearts of transgenic mice.