title: The role of human achaete-scute homolog-1 in medullary thyroid cancer cells.
abstract: BACKGROUND
  Human achaete-scute homolog-1 (hASH1) is a transcription factor that is expressed highly in neuroendocrine tumors such as medullary thyroid cancer (MTC). Thyroid C-cells do not develop in hASH1 knockout mice, which suggests that hASH1 is essential for normal C-cell development.
  
  
  METHODS
  To determine the effect of raf-1 induction on hASH1 and hormone production, we used an estrogen inducible raf-1 construct in MTC cell line (TT) cells (TT-raf cells). TT or TT-raf cells were treated with control or 1 microM estradiol. After 48 hours, the cells were analyzed for levels of hASH1 and chromogranin A by Western blotting and for calcitonin production by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Activation of raf-1 in the TT-raf cells resulted in high levels of phosphorylated MEK and ERK1/2, a morphologic transdifferentiation, and a decrease in chromogranin A and calcitonin levels that are associated with a reduction in hASH1 production. Furthermore, using MEK inhibitors, we demonstrated that these raf-1-mediated changes are dependent on MEK but not ERK1/2 activation.
  
  
  CONCLUSIONS
  hASH1 down-regulation by raf-1 in MTC cells is associated with a significant decrease in hormone production. Thus, hASH1 appears to be important in the endocrine phenotype of MTC tumors and may serve as a molecular target for the treatment of patients with MTC.
authors.affiliation: Department of Surgery, The University of Wisconsin Medical School and the University of Wisconsin Comprehensive Cancer Center, 600 Highland Avenue, Madison, WI 53792, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Sippel
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Carpenter
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Kunnimalaiyaan
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins; D002116:Calcitonin / Q000378:metabolism; D018276:Carcinoma, Medullary / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D006801:Humans; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002116:Calcitonin; D004268:DNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D014157:Transcription Factors; C065500:ASCL1 protein, human