CELL PROLIFERATION FOXOs Connect Smads and PI3K Pathways

Transforming growth factor-ß (TGF-ß) activates Smads to regulate the expression of many genes. One cellular response is cytostatis, cessation of proliferation, which involves TGF-ß-mediated repression of c-myc expression and stimulation of p21Cip1. Seoane et al. show that full induction of p21Cip1 expression by TGF-ß requires both the Smad2/3 complex and Smad4, as well as members of the subfamily of Forkhead proteins (FOXOs). The Smad-binding region of the p21Cip1 promoter contains a Forkhead-binding element (FHBE), and chromatin immunoprecipitation analysis (ChIP) showed that both Smads and FOXO3 bound to the p21Cip1 promoter. In a human keratinocyte cell line (HaCaT cells), the Smad2/3-Smad4 complex coprecipitated with FOXO1, FOXO3, or FOXO4, when stimulated with TGF-ß. FOXOs represent a point of intersection between the phosphoinositide 3-kinase (PI3K) and TGF-ß pathways, because FOXOs are phosphorylated by the PI3K-activated kinase Akt (phosphorylated FoxOs are inhibited by sequestration in the cytosol). In addition, the Smad2/3-Smad4 and FOXO complex was also the target for the inhibitory member of the Forkhead family, FoxG1. These proteins all formed a complex, and in the presence of FoxG1, cells were resistant to the cytostatic effects of TGF-ß, and p21Cip1 expression was not increased. During development, the cytostatic actions of TGF-ß must be carefully controlled to prevent premature loss of progenitor cells, which is highlighted by the reduced cerebral brain region in foxg1^—/— mice. During cancer progression, loss of responsiveness to the cytostatic effects of TGF-ß may arise because of enhanced PI3K signaling, like that seen in human glioma and glioblastoma, which frequently contain a mutant Pten gene.

J. Seoane, H.-V. Le, L. Shen, S. A. Anderson, J. Massagué, Integration of Smad and Forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117, 211-223 (2004). [Online Journal]

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