Fra-1 promotes growth and survival in RAS-transformed thyroid cells by controlling cyclin A transcription.
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.
Casalino
Laura
L
A Buzzati Traverso Institute of Genetics and Biophysics, CNR, Naples, Italy. casalino@igb.cnr.it
Bakiri
Latifa
L
Talotta
Francesco
F
Weitzman
Jonathan B
JB
Fusco
Alfredo
A
Yaniv
Moshe
M
Verde
Pasquale
P
D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002470:Cell Survival; D002999:Clone Cells; D019925:Cyclin A / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D016195:G2 Phase; D011905:Genes, ras; D008938:Mitosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D013961:Thyroid Gland / Q000166:cytology* / Q000254:growth & development*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D000099169:Fos-Related Antigen 1
D018797:Cell Cycle Proteins; D019925:Cyclin A; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D000099169:Fos-Related Antigen 1