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Fra-1 promotes growth and survival in RAS-transformed thyroid cells by controlling cyclin A transcription.
- Source :
-
The EMBO journal [EMBO J] 2007 Apr 04; Vol. 26 (7), pp. 1878-90. Date of Electronic Publication: 2007 Mar 08. - Publication Year :
- 2007
-
Abstract
- Fra-1 is frequently overexpressed in epithelial cancers and implicated in invasiveness. We previously showed that Fra-1 plays crucial roles in RAS transformation in rat thyroid cells and mouse fibroblasts. Here, we report a novel role for Fra-1 as a regulator of mitotic progression in RAS-transformed thyroid cells. Fra-1 expression and phosphorylation are regulated during the cell cycle, peaking at G2/M. Knockdown of Fra-1 caused a proliferative block and apoptosis. Although most Fra-1-knockdown cells accumulated in G2, a fraction of cells entering M-phase underwent abortive cell division and exhibited hallmarks of genomic instability (micronuclei, lagging chromosomes and anaphase bridges). Furthermore, we established a link between Fra-1 and the cell-cycle machinery by identifying cyclin A as a novel transcriptional target of Fra-1. During the cell cycle, Fra-1 was recruited to the cyclin A gene (ccna2) promoter, binding to previously unidentified AP-1 sites and the CRE. Fra-1 also induced the expression of JunB, which in turn interacts with the cyclin A promoter. Hence, Fra-1 induction is important in thyroid tumorigenesis, critically regulating cyclin expression and cell-cycle progression.
- Subjects :
- Animals
Apoptosis
Cell Cycle Proteins metabolism
Cell Line, Transformed
Cell Proliferation
Cell Survival
Clone Cells
Cyclin A metabolism
Flow Cytometry
G2 Phase
Mitosis
Promoter Regions, Genetic genetics
Protein Binding
Proto-Oncogene Proteins c-fos biosynthesis
Proto-Oncogene Proteins c-fos genetics
Proto-Oncogene Proteins c-jun metabolism
RNA Interference
Rats
Transcriptional Activation genetics
Cyclin A genetics
Genes, ras
Proto-Oncogene Proteins c-fos metabolism
Thyroid Gland cytology
Thyroid Gland growth & development
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 0261-4189
- Volume :
- 26
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The EMBO journal
- Publication Type :
- Academic Journal
- Accession number :
- 17347653
- Full Text :
- https://doi.org/10.1038/sj.emboj.7601617