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  • The EMBO Journal (2007) 26, 1878 - 1890
  • doi:10.1038/sj.emboj.7601617

Published online: 8 March 2007

Fra-1 promotes growth and survival in RAS-transformed thyroid cells by controlling cyclin A transcription

Laura Casalino1,2, Latifa Bakiri3, Francesco Talotta1, Jonathan B Weitzman2, Alfredo Fusco4, Moshe Yaniv2 and Pasquale Verde1

  1. Institute of Genetics and Biophysics 'A Buzzati Traverso', CNR, Naples, Italy
  2. Unit of Gene Expression and Disease, Department of Developmental Biology, Pasteur Institute, Paris, France
  3. Research Institute of Molecular Pathology, Vienna, Austria
  4. Department of Molecular and Cellular Pathology, University 'Federico II', Naples, Italy

Correspondence to:

Laura Casalino, Institute of Genetics and Biophysics 'A Buzzati Traverso', CNR, Naples, Italy. Tel.: +39 0816132452; Fax: +39 0816132706; E-mail: verde@igb.cnr.it

Pasquale Verde, Institute of Genetics and Biophysics 'A Buzzati Traverso', CNR, Naples, Italy. E-mail: casalino@igb.cnr.it

Received 2 August 2006; Accepted 25 January 2007

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.

  • Keywords:

    • AP-1,
    • cyclin A,
    • Fra-1,
    • RAS transformation,
    • thyroid