Abstract
Human tumors of various tissue origins show an intriguing over-expression of genes not considered oncogenes, such as that encoding Troponin-I (TnI), a well-known muscle protein. Out of the three TnI genes known in humans, the slow form, TNNI1, is affected the most. Drosophila has only one TnI gene, wupA. Here, we studied excess- and loss-of function of wupA in Drosophila, and assayed TNNI1 down regulation in human tumors growing in mice. Drosophila TnI excess-of-function increases proliferation and potentiates oncogenic mutations in Ras, Notch and Lgl genes. By contrast, TnI loss-of-function reduces proliferation and antagonizes the overgrowth due to these oncogenic mutations. Troponin-I defective cells undergo Flower- and Sparc-dependent cell competition. TnI can localize to the nucleus and its excess elicits transcriptional up-regulation of InR, Rap1 and Dilp8, which is consistent with the increased cell proliferation. Human tumor cell lines treated with a human Troponin-I peptide arrest in G0/G1. In addition, proliferation of non-small-cell lung carcinoma xenografts in mice is restrained by TNNI1 down-regulation. Thus, Troponin-I reveals a novel function in cell proliferation that may be of therapeutic interest in certain types of cancer.
Highlights
Troponin-I (TnI) binds F-actin to regulate muscle contraction through a complex with Troponin-C, Troponin-T and Tropomyosin which decorates the thin filaments of the sarcomere at regular intervals [1,2,3]
Following the discovery that fly TnI is expressed in virtually all cell types, we explored the possible involvement of the human homologue in pathology
We noticed a significant proportion of cases with altered expression of Troponin-I (TNNI) genes in the Catalogue of Somatic Mutations in Cancer, TNNI1 in lung, ovary and endometrium tumors, among others (Figure 1A, 1B)
Summary
Troponin-I (TnI) binds F-actin to regulate muscle contraction through a complex with Troponin-C, Troponin-T and Tropomyosin which decorates the thin filaments of the sarcomere at regular intervals [1,2,3]. The unexpected discovery of TnI in non-muscle cells [4] raised questions about its role in general cell biology. TnI in S2 cell cultures traffics between the nucleus and the cytoplasm using a sumoylationdependent mechanism [4]. Vertebrate TnI had been detected in cartilage as an anti-angiogenic factor, which, indirectly, would prevent metastatic liver growth in a mouse model of pancreatic primary tumor [5,6]. In spite of these observations, the role of TnI outside the well characterized muscle cells had remained enigmatic
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