Biomedical subjects

Mika Yageta

Publications and source records attributed to Mika Yageta.

5 recordsLinked to original sources

PubMed2003

Isolation of the mouse Tsll1 and Tsll2 genes, orthologues of the human TSLC1-like genes 1 and 2 (TSLL1 and TSLL2).

We have recently identified the human TSLL1 and TSLL2 genes, which are highly homologous to the human lung tumor suppressor gene, TSLC1. Loss of expression of the TSLL1 or TSLL2 in several cancers suggests that these genes could also act as tumor suppressors. Here, we report the isolation of the mouse orthologous genes, Tsll1 and Tsll2. The Tsll1 and Tsll2 cDNAs contain a single open reading frame of 1188 and 1164 bp encoding a putative immunoglobulin-like cell adhesion molecules of 396 and 388 amino acids, which display 95% and 98% identity with those of human TSLL1 and TSLL2, respectively. The Tsll1 and Tsll2 genes are both composed of nine exons and mapped on mouse chromosome 1q H2-H4 and on 7q A3-B2, respectively, both of which conserve syntenies with human chromosomes 1q and 19q. Like the human TSLL1, the mouse Tsll1 was expressed exclusively in the brain and neurogenic cells, while Tsll1 expression was lost in one of four rodent neuroblastoma cell lines. Tsll2 was expressed in the brain and several organs including the kidney and liver, whereas loss of Tsll2 expression was detected in some rodent cancer cells derived from these tissues. Furthermore, both murine TSLL1 and TSLL2 proteins were expressed on the plasma membrane, especially at the cell-cell attached site. These data, together with their strong conservation during the vertebrate evolution, suggest that TSLL1and TSLL2 could play an important role in cell-cell interaction as well as in tumor suppression.

Amino Acid Sequence↗

PubMed2003

Association of a lung tumor suppressor TSLC1 with MPP3, a human homologue of Drosophila tumor suppressor Dlg.

We have previously identified the tumor suppressor in lung cancer 1 (TSLC1) gene as a novel tumor suppressor in human non-small cell lung cancer (NSCLC) by functional complementation. TSLC1 encodes a membrane glycoprotein belonging to an immunoglobulin superfamily and participates in cell adhesion. A truncating mutation of the TSLC1 corresponding to its cytoplasmic domain in a primary NSCLC tumor suggests that this domain is important for tumor suppressor activity. Here, we report that TSLC1 directly associates with MPP3, one of the human homologues of a Drosophila tumor suppressor gene, Discs large (Dlg). This interaction was dependent on the presence of a PDZ-binding motif at the carboxyl terminus of TSLC1. Furthermore, TSLC1 and MPP3 were colocalized at the cell-cell attachment sites in both a low and a high cell density. The MPP3 gene was expressed in normal lung as well as in many tissues examined except for peripheral blood lymphocytes but lost its expression in one of the nine NSCLC cell lines. These results suggest that TSLC1 and MPP3 are involved in the same cascade of cell-cell interaction, and that the disruption of this cascade might lead cells to malignant growth and tumor formation in lung cancer.

Amino Acid Sequence↗

PubMed2002

Direct association of TSLC1 and DAL-1, two distinct tumor suppressor proteins in lung cancer.

The tumor suppressor gene TSLC1, which we recently identified in human non-small cell lung cancer, encodes a membrane glycoprotein of the immunoglobulin superfamily. Here, we report that TSLC1 directly associates with DAL-1, a gene product of another lung tumor suppressor belonging to the protein 4.1 family. TSLC1 additionally interacts with the actin filament through DAL-1 at the cell-cell attached site where the complex formation of TSLC1 and DAL-1 is dependent on the integrity of actin cytoskeleton. Redistribution of both TSLC1 and DAL-1 to the newly generated membrane ruffling areas suggests that these proteins are also involved in cell motility accompanying the actin rearrangement. Furthermore, restoration of TSLC1 expression strongly suppressed the metastasis of a human non-small cell lung cancer cell line, A549, from the spleen to the liver in nude mice. These findings, together with frequent loss of their expression in lung cancers, suggest that TSLC1 and DAL-1 play a critical role in the same pathway involved in the suppression of lung tumor formation and metastasis.

Actins↗

PubMed2002

The tumor suppressor protein TSLC1 is involved in cell-cell adhesion.

TSLC1 is a tumor suppressor gene encoding a member of the immunoglobulin (Ig) superfamily. The significant homology of its extracellular domain with those of other Ig superfamily cell adhesion molecules (IgCAMs) has raised the possibility that TSLC1 participates in cell-cell interactions. In this study, the physiological properties of TSLC1 were investigated in Madin-Darby canine kidney (MDCK) cells expressing TSLC1 tagged with green fluorescent protein (GFP) as well as in the cells that express endogenous TSLC1. Biochemical analysis has revealed that TSLC1 is an N-linked glycoprotein with a molecular mass of 75 kDa and that it forms homodimers through cis interaction within the plane of the cell membranes. Confocal laser scanning microcopy of the cells expressing TSLC1 showed the localization patterns characteristic to adhesion molecules. At the beginning of cell attachment, TSLC1 accumulated in interdigitated structures at cell-cell boundaries, but, when cells reached a confluence, TSLC1 was distributed all along the cell membranes. In polarized cells, TSLC1 was recruited to the lateral membrane, implying trans interaction of TSLC1 between neighboring cells. In support of this notion, MDCK cells expressing TSLC1-GFP showed a significant level of cell aggregation in the absence or presence of Ca(2+) and Mg(2+). Taken together, these results indicate that TSLC1 mediates intracellular adhesion through homophilic interactions in a Ca(2+)/Mg(2+)-independent manner.

Calcium↗

PubMed2002

Cdc6 requires anchorage for its expression.

Fibroblasts need anchorage to extracellular matrix to transit from G1 to S phase, but no longer after oncogenic transformation. Here we report that Cdc6 protein essential for the activation of replication origins requires anchorage or oncogenic stimulation for its execution. Upon anchorage loss, Cdc6 expression is shut off both transcriptionally and post-transcriptionally in a rat fibroblast despite enforced activation of E2F-dependent promoters. However, stimulation of this cell with oncogenic growth factors suppresses this shutoff and concurrently activates Cdk2 and Cdk6/4, thereby overriding the anchorage requirement for the G1-S transition and consequently enabling cells to perform anchorage-independent S phase entry. Analysis with enforced expression of Cdc6 indicates that the G1 cyclin-dependent kinases and Cdc6 constitute major cell cycle targets for the restriction of the G1-S transition by anchorage loss.

Animals↗