The molecular basis for tropomyosin isoform diversity

Lees‐Miller, James P.; Helfman, David M.

doi:10.1002/bies.950130902

Cited by 341 publications

(289 citation statements)

References 48 publications

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“…T ropomyosin is an actin-binding protein found in virtually all eukaryotic cells (1). In sarcomeric muscle it acts together with troponin to regulate myosin access to the actin filament (2).…”

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confidence: 99%

Mdm20 protein functions with Nat3 protein to acetylate Tpm1 protein and regulate tropomyosin–actin interactions in budding yeast

Singer

Shaw

2003

Proc. Natl. Acad. Sci. U.S.A.

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The evolutionarily conserved Mdm20 protein (Mdm20p) plays an important role in tropomyosin-F-actin interactions that generate actin filaments and cables in budding yeast. However, Mdm20p is not a structural component of actin filaments or cables, and its exact function in cable stability has remained a mystery. Here, we show that cells lacking Mdm20p fail to N-terminally acetylate Tpm1p, an abundant form of tropomyosin that binds and stabilizes actin filaments and cables. The F-actin-binding activity of unacetylated Tpm1p is reduced severely relative to the acetylated form. These results are complemented by the recent report that Mdm20p copurifies with one of three acetyltransferases in yeast, the NatB complex. We present genetic evidence that Mdm20p functions cooperatively with Nat3p, the catalytic subunit of the NatB acetyltransferase. These combined results strongly suggest that Mdm20p-dependent, N-terminal acetylation of Tpm1p by the NatB complex is required for Tpm1p association with, and stabilization of, actin filaments and cables.

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mentioning

confidence: 99%

Mdm20 protein functions with Nat3 protein to acetylate Tpm1 protein and regulate tropomyosin–actin interactions in budding yeast

Singer

Shaw

2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Tropomyosin isoform expression involves the use of multiple genes, but diversity is also generated by alternative processing of mRNA (Lees-Miller and Helfman, 1991). Four different tropomyosin genes have been characterised in mammals (a-TM, fl-TM, and hTMnm).…”

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confidence: 99%

“…It has been suggested that down-regulation of tropomyosin expression in tumour cells may decrease microfilament stability owing to increased susceptibility to depolymerising factors. The loss of microfilament structure may lead to altered cell shape, motility and altered interaction with extracellular supporting elements (Cooper et al, 1987;Lees-Miller and Helfman, 1991). Interestingly, forced expression of tm 1 or tm 2 in tumour cells by the introduction of cDNA expression vectors suppresses malignant growth (Prasad et al, 1993) or causes an altered cellular morphology (Takenaga and Masuda, 1994).…”

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confidence: 99%

Expression of tropomyosin isoforms in benign and malignant human breast lesions

Franzén

Linder²,

Uryu³

et al. 1996

Br J Cancer

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Summary High molecular weight tropomyosins (tms) are commonly down-regulated in fibroblasts transformed by oncogenes. Previous studies have also demonstrated that specific tm isoforms are downregulated in human breast carcinoma cell lines. We examined tropomyosin isoforms in cells prepared from noncancerous breast lesions and primary human breast carcinomas. The average level of expression of all three high molecular weight tm isoforms (tm 1-3) in carcinomas was generally found to be less than 25% of that observed in non-cancerous breast lesions. Interestingly, the expression of tm 1 was found to be 1.7-fold higher in primary tumours with metastatic spread to axillary lymph nodes compared with primary tumours with no evidence of metastasis (P<0.05). Similarly, tm 1 expression was higher in two 12V-H-ras transformed fibroblast cell lines capable of experimental metastasis compared with three weakly metastatic cell lines. We conclude from these studies that expression of high molecular weight tm isoforms is low in primary breast carcinomas, and that metastatic tumours express relatively high levels of tm 1.

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“…Such cross-linked heterodimers occur in muscle cells (Lehrer and Joseph, 1987) because the tropomyosin p isoform of muscle cells contains both Cys36 and Cysl90 which would permit their formation. The observation raises the possibility that NIH3T3 cells express, in addition to the high-M, isoforms typical of fibroblasts, a significant amount of an alternative splice product (Lees-Miller and Helfman, 1991) typical of muscle cells. Since, as noted below, this form was produced to a much lower degree in other normal fibroblasts, its prominence in NIH3T3 cells may be a peculiarity of that cell line, or of the particular cultivar used in our laboratory.…”

Section: Tropomyosin Dimer Formation In Cultured Fibroblastsmentioning

confidence: 98%

“…Tropomyosins are a family of ubiquitous actin-binding proteins with extensive a-helical structure that play a welldefined role in muscle contraction (Leavis and Gergely, 1984 ;Payne and Rudnick, 1985 ;Lees-Miller and Helfman, 1991). In non-muscle cells, the role of tropomyosins is less clearly understood, and it is generally thought that they are involved in stabilization of actin microfilaments which, in turn, play an important role in maintaining cell shape, motil-ity, and interaction with extracellular supporting elements (Pollard et al, 1976;CBtC, 1983;Stossel et al, 1985).…”

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confidence: 99%

Expression, Cytoskeletal Utilization and Dimer Formation of Tropomyosin Derived from Retroviral‐Mediated cDNA Transfer

Prasad

Fuldner

Braverman

et al. 1994

European Journal of Biochemistry

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Expression of the tropomyosin-1 isoform was enhanced by cDNA transfer in non-transformed murine 3T3 fibroblasts and also in v-Ki-ras transformed fibroblasts in which native tropomyosin-1 expression had been reduced and tropomyosin-2 synthesis virtually eliminated by action of the oncogene. The level of synthesis of insert-derived tropomyosin-1 was similar in normal and transformed transductants (3 -5 times normal levels). The high level of insert-derived tropomyosin-1 expression resulted in a considerable increase in tropomyosin-1 utilization in the cytoskeleton of transformed cells, but this expression still did not reach normal levels, suggesting an oncogenerelated inhibition of tropomyosin utilization. A large proportion of newly synthesized native tropomyosin-1 in normal, unmodified fibroblasts appeared in homodimers which, upon prolonged incubation, were largely converted to the heterodimers. Excess tropomyosin-1 derived from the inserted cDNA also appeared largely as the homodimer in both normal and transformed cells. This homodimer was utilized effectively in the formation of cytoskeletal structures but was partially converted to heterodimer by chain exchange. Under steady-state conditions, approximately 33 % of the cytoskeletal tropomyosin-1 -containing dimers were homodimers, compared to approximately 10% in normal fibroblasts. The results show that the increased amount of tropomyosin-1 homodimer entering the cytoskeleton under conditions of tropomyosin-1 excess, results in an atypical microfilament composition. The effect of this excess of tropomyosin-1 homodimers on stability or function of microfilament fibers remains to be determined. The results also confirm that the mechanisms of rapid homodimer formation with conversion to heterodimers by chain exchange, known from in vitro studies, also occur in vivo.

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The molecular basis for tropomyosin isoform diversity

Abstract: The tropomyosins are a family of actin filament binding proteins. In multicellular animals, they exhibit extensive cell type specific isoform diversity. In this essay we discuss the genetic mechanisms by which this diversity is generated and its possible significance to cellular function.

Cited by 341 publications

References 48 publications

Mdm20 protein functions with Nat3 protein to acetylate Tpm1 protein and regulate tropomyosin–actin interactions in budding yeast

Mdm20 protein functions with Nat3 protein to acetylate Tpm1 protein and regulate tropomyosin–actin interactions in budding yeast

Expression of tropomyosin isoforms in benign and malignant human breast lesions

Expression, Cytoskeletal Utilization and Dimer Formation of Tropomyosin Derived from Retroviral‐Mediated cDNA Transfer

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