TSC-22 (TGF-beta stimulated clone-22): a novel molecular target for differentiation-inducing therapy in salivary gland cancer.
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.
Kawamata
H
H
Department of Oral and Maxillofacial Surgery, Dokkyo University School of Medicine, Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Japan. h-kawama@dokkyomed.ac.jp
Fujimori
T
T
Imai
Y
Y
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008969:Molecular Sequence Data; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D012468:Salivary Gland Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*
D012097:Repressor Proteins; C099726:TSC22D1 protein, human; C490983:Tgfb1i4 protein, mouse