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The transcription factor FLI1 promotes cancer progression by affecting cell cycle regulation.
Miao, Beiping; Bauer, Andrea S; Hufnagel, Katrin; Wu, Yenan; Trajkovic-Arsic, Marija; Pirona, Anna C; Giese, Nathalia; Taipale, Jussi; Siveke, Jens T; Hoheisel, Jörg D; Lueong, Smiths.
Afiliação
  • Miao B; Division of Functional Genome Analysis (B070), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Bauer AS; Medical Faculty, University of Heidelberg, Heidelberg, Germany.
  • Hufnagel K; Division of Functional Genome Analysis (B070), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Wu Y; Infections and Cancer Epidemiology (F022), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Trajkovic-Arsic M; Division of Functional Genome Analysis (B070), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Pirona AC; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
  • Giese N; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Taipale J; Division of Functional Genome Analysis (B070), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Siveke JT; Research Laboratory of the European Pancreas Centre (EPZ) Integrative Oncology Group, University Clinic Heidelberg, Heidelberg, Germany.
  • Hoheisel JD; Division of Functional Genomics, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Sweden.
  • Lueong S; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
Int J Cancer ; 147(1): 189-201, 2020 07 01.
Article em En | MEDLINE | ID: mdl-31846072
ABSTRACT
Binding of transcription factors to mutated DNA sequences is a likely regulator of cancer progression. Noncoding regulatory mutations such as those on the core promoter of the gene encoding human telomerase reverse transcriptase have been shown to affect gene expression in cancer. Using a protein microarray of 667 transcription factor DNA-binding domains and subsequent functional assays, we looked for transcription factors that preferentially bind the mutant hTERT promoter and characterized their downstream effects. One of them, friend leukemia integration 1 (FLI1), which belongs to the E26 transforming-specific family of transcription factors, exhibited particularly strong effects with respect to regulating hTERT expression, while the even better binding ELK3 did not. Depletion of FLI1 decreased expression of the genes for cyclin D1 (CCND1) and E2F transcription factor 2 (E2F2) resulting in a G1/S cell cycle arrest and in consequence a reduction of cell proliferation. FLI1 also affected CMTM7, another gene involved in G1/S transition, although by another process that suggests a balanced regulation of the tumor suppressor gene's activity via opposing regulation processes. FLI1 expression was found upregulated and correlated with an increase in CCND1 expression in pancreatic cancer and brain tumors. In non-neoplastic lung cells, however, FLI1 depletion led to rapid progression through the cell cycle. This coincides with the fact that FLI1 is downregulated in lung tumors. Taken together, our data indicate a cell cycle regulatory hub involving FLI1, hTERT, CCND1 and E2F2 in a tissue- and context-dependent manner.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína Proto-Oncogênica c-fli-1 / Neoplasias Limite: Humans Idioma: En Revista: Int J Cancer Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína Proto-Oncogênica c-fli-1 / Neoplasias Limite: Humans Idioma: En Revista: Int J Cancer Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Alemanha