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Fra‐1 promotes growth and survival in RAS ‐transformed thyroid cells by controlling cyclin A transcription
Author(s) -
Casalino Laura,
Bakiri Latifa,
Talotta Francesco,
Weitzman Jonathan B,
Fusco Alfredo,
Yaniv Moshe,
Verde Pasquale
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601617
Subject(s) - biology , transcription (linguistics) , microbiology and biotechnology , transcription factor , cyclin , cancer research , thyroid , cell growth , genetics , cell cycle , gene , philosophy , linguistics
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.