Editors' ChoiceCell Cycle Regulation

Forkhead Transcription Factors Block Cell Cycle

Science's STKE  18 Apr 2000:
Vol. 2000, Issue 28, pp. tw1
DOI: 10.1126/stke.2000.28.tw1

Forkhead proteins are involved in controlling the life span of nematodes. Their activation through phosphorylation by protein kinase B (PKB) is thought to protect cells from cell death (see news and views article by Pulverer). Medema et al. show that in mammalian cells Forkhead transcription factors regulate the cell cycle by inducing expression of the cyclin-cyclin-dependent kinase inhibitor p27kip1. Growth of transformed cells is suppressed by overexpression of the Forkhead family members, AFX or FKHR-L1, and the suppression is dependent on the ability of AFX to bind DNA. Transfected cells arrest in G1, but such arrest can be blocked by treating the cells with insulin to stimulate the PKB pathway. PKB phosphorylates and inactivates AFX. The ability to induce G1 arrest appears to be dependent on functional p27kip1 because expression of AFX in immortalized mouse embryonic fibroblasts from p27kip1 knockout mice exhibit decreased growth arrest and decreased inhibition of cyclin E kinase activity. The results indicate that Forkhead transcription factors are targets of the PKB pathway and are important regulators of cellular proliferation as well as cell death and that both processes may be essential for formation of cancer cells.

Medema, R.H., Kops, G.J.P.L., Bos, J.L., and Burgering, B.M.T. (2000) AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404: 782-787. [Online Journal]

Pulverer, B. (2000) An arresting tale. Nature 404: 714. [Online Journal]