TSC-22 (TGF-β Stimulated Clone-22): A Novel Molecular Target for Differentiation-Inducing Therapy in Salivary Gland Cancer

Abstract

TSC-22 (Transforming growth factor-beta stimulated clone-22) was originally isolated as a TGF-beta-inducible gene in mouse osteoblastic cells. TSC-22 encodes a putative transcriptional regulator containing a leucine zipper-like structure. Several differentiation-inducing stimuli up-regulate the TSC-22 gene. Furthermore, TSC-22 acts as an effector that integrates multiple extracellular signals during embryogenesis of Drosophila and mouse. Separately, we identified TSC-22 cDNA as an anti-cancer drug (vesnarinone)-inducible gene in a human salivary gland cancer cell line, TYS. Vesnarinone is known to have a differentiation-inducing activity in several cell types. We showed that TSC-22 negatively regulated the growth of TYS cells, and that down-regulation of TSC-22 played a major role in the salivary gland tumorigenesis. Subsequently, we found that artificial overexpression of TSC-22 enhanced chemosensitivity and radiation-sensitivity by inducing apoptosis in TYS cells. Recently, we isolated TSC-22 genomic DNA and analyzed the transcriptional and post-transcriptional regulation of the TSC-22 gene. Then, we confirmed by the luciferase reporter assay that several differentiation-inducing stimuli directly activated the promoter region of TSC-22 gene. Now we are investigating the chemical compounds, which could enhance the transcription of the TSC-22 gene. Thus, because TSC-22 is a key molecule for differentiation of several cells, it can be used as a molecular target for cancer differentiation therapy in salivary gland cancer.

TSC-22 Promotes Transforming Growth Factor β-Mediated Cardiac Myofibroblast Differentiation by Antagonizing Smad7 Activity

“…TSC-22 belongs to a group of proteins that contain a leucine zipper motif and a TSC box in the middle with divergent N termini and C termini (18,19). We found that its N-terminal region (aa 1 to 44) is important for both its interaction with T␤RI and Smad7 and promotion of TGF-␤ signaling.…”

“…TSC-22 was originally identified as a TGF-␤-responsive gene in mouse osteoblastic MC3T3E1 cells (30). Subsequently, it was also found to be induced by TGF-␤ in several other cell lines, such as HSC-39 human gastric carcinoma cells, TYS salivary gland cancer cells, and FaO hepatoma cells (18). It has been reported that TSC-22 inhibits cell proliferation and induces differentiation and apoptosis (5,24).…”

“…Consistently, gene targeting of TSC-22 enhanced the proliferation of hematopoietic precursor cells (HPCs) (40). In addition, TSC-22 was also reported to promote cell differentiation and apoptosis (7,18). Moreover, the Drosophila homolog of TSC-22 was suggested to be in the same genetic pathway as Dpp (a bone morphogenetic protein [BMP] homolog) during fly eye development (33), and it was also shown to induce erythroid cell differentiation by facilitating TGF-␤ signaling (4).…”

“…2G). TSC-22 belongs to the TSC-22 protein family, with the conserved TSC box and a leucine zipper (LZ) motif in the middle and flexible N-terminal and C-terminal regions (18,19). Domain mapping analysis revealed that the N terminus of TSC-22 mediates its association with T␤RI ( Fig.…”

“…Moreover, the Drosophila homolog of TSC-22 was suggested to be in the same genetic pathway as Dpp (a bone morphogenetic protein [BMP] homolog) during fly eye development (33), and it was also shown to induce erythroid cell differentiation by facilitating TGF-␤ signaling (4). TSC-22 is an evolutionarily conserved cytoplasmic protein and belongs to the TSC-22 protein family, which is characterized by the conserved TSC box and a leucine zipper (LZ) motif in the middle, while the N termini and the C termini in family members are divergent (18,19).…”