Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: Role in epithelial cancer cell invasion, proliferation and nuclear regulation (original) (raw)

Abstract

Using differential cDNA library screening techniques based on metastatic and nonmetastatic rat mammary adenocarcinoma cell lines, we previously cloned and sequenced the metastasis-associated gene mta1. Using homology to the rat mta1 gene, we cloned the human MTA1 gene and found it to be over-expressed in a variety of human cell lines (breast, ovarian, lung, gastric and colorectal cancer but not melanoma or sarcoma) and cancerous tissues (breast, esophageal, colorectal, gastric and pancreatic cancer). We found a close similarity between the human MTA1 and rat mta1 genes (88% and 96% identities of the nucleotide and predicted amino acid sequences, respectively). Both genes encode novel proteins that contain a proline rich region (SH3-binding motif), a putative zinc finger motif, a leucine zipper motif and 5 copies of the SPXX motif found in gene regulatory proteins. Using Southern blot analysis the MTA1 gene was highly conserved, and using Northern blot analysis MTA1 transcripts were found in virtually all human cell lines (melanoma, breast, cervix and ovarian carcinoma cells and normal breast epithelial cells). However, the expression level of the MTA1 gene in normal breast epithelial cells was ∼ 50% of that found in rapidly growing adenocarcinoma and atypical epithelial cell lines. Experimental inhibition of MTA1 protein expression using antisense phosphorothioate oligonucleotides resulted in inhibition of growth and invasion of human MDA-MB-231 breast cancer cells with relatively high MTA1 expression. Furthermore, the MTA1 protein was localized in the nuclei of cells transfected with a mammalian expression vector containing a full-length MTA1 gene. Although some MTA1 protein was found in the cytoplasm, the vast majority of MTA1 protein was localized in the nucleus. Examination of recombinate MTA1 and related MTA2 proteins suggests that MTA1 protein is a histone deacetylase. It also appears to behave like a GATA-element transcription factor, since transfection of a GATA-element reporter into _MTA1_-expressing cells resulted in 10–20-fold increase in reporter expression over poorly _MTA1_-expressing cells. Since it was reported that nucleosome remodeling histone deacetylase complex (NuRD complex) involved in chromatin remodeling contains MTA1 protein and a MTA1-related protein (MTA2), we examined NuRD complexes for the presence of MTA1 protein and found an association of this protein with histone deacetylase. The results suggest that the MTA1 protein may serve multiple functions in cellular signaling, chromosome remodeling and transcription processes that are important in the progression, invasion and growth of metastatic epithelial cells.

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Authors and Affiliations

  1. The Institute for Molecular Medicine, Huntington Beach, California, USA
    Garth L. Nicolson
  2. Department of Obstetrics and Gynecology, Nagoya University School of Medicine, Nagoya, Japan
    Akihiro Nawa & Katsuhiko Nishimori
  3. Department of Gastroenterorogic Surgery, National Kyushu Cancer Center, Japan
    Yasushi Toh
  4. Laboratory of Molecular Biology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
    Shigeki Taniguchi
  5. Ein Shams University School of Medicine, Cairo, Egypt
    Amr Moustafa

Authors

  1. Garth L. Nicolson
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  2. Akihiro Nawa
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  3. Yasushi Toh
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  4. Shigeki Taniguchi
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  5. Katsuhiko Nishimori
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  6. Amr Moustafa
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Nicolson, G.L., Nawa, A., Toh, Y. et al. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: Role in epithelial cancer cell invasion, proliferation and nuclear regulation.Clin Exp Metastasis 20, 19–24 (2003). https://doi.org/10.1023/A:1022534217769

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