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Toshiyuki Yoshio, Tsuyoshi Morita, Masahiko Tsujii, Norio Hayashi, Kenji Sobue, MRTF-A/B suppress the oncogenic properties of v-ras- and v-src-mediated transformants, Carcinogenesis, Volume 31, Issue 7, July 2010, Pages 1185–1193, https://doi.org/10.1093/carcin/bgq065
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Abstract
Two members of the myocardin protein family, myocardin-related transcription factor (MRTF)-A and MRTF-B are co-activators of serum response factor (SRF). We recently reported that MRTF-A/B activates the transcription of several actin cytoskeletal/focal adhesion genes SRF dependently, thereby enhancing the formation of stress fibers and focal adhesions. Here, we showed that the levels of caldesmon and tropomyosin, both SRF/MRTF-regulated actin cytoskeletal proteins, were reduced in rat intestinal epithelial (RIE) cell lines that had been transformed with oncogenic ras (RIE-ras) or src (RIE-src) compared with their parental cell line. These cells exhibited morphological abnormalities associated with a disorganized actin cytoskeleton. The serum-stimulated nuclear translocation of MRTF-A/B was suppressed in the RIE-ras and RIE-src cells. However, the transient expression of constitutively active (CA) MRTF-A or MRTF-B reversed the reduced expression levels of caldesmon and tropomyosin and the associated morphological phenotypes. We isolated stable CA-MRTF-A-expressing cell lines from transfected RIE-ras and RIE-src cells and found that their levels of caldesmon and tropomyosin were close to those of untransformed RIE cells. Their morphologies were also normal, with a flattened cell shape and well-developed stress fibers. The CA-MRTF-A-expressing RIE-ras and RIE-src lines also showed lower invasiveness and anchorage-independent growth than their transformed parental cells, in vitro . In vivo , CA-MRTF-A expression suppressed tumor formation and reduced liver metastases. Therefore, we concluded that MRTF-A/B are potent repressors of cancer progression and metastasis and may be good targets for cancer therapy.
- actins
- phenotype
- tropomyosin
- serum response factor
- epithelium
- cell lines
- cytoskeletal proteins
- cytoskeleton
- focal adhesions
- genes
- intestines
- neoplasm metastasis
- parent
- stress fibers
- neoplasms
- rats
- transcription factor
- liver metastases
- transcriptional activation
- transcriptional repression
- cancer therapy
- nuclear translocation
- tumor progression