Identification of FOXC1 as a TGF-beta1 responsive gene and its involvement in negative regulation of cell growth.
We cloned the forkhead box C1 (FOXC1) gene, a member of the forkhead/winged-helix transcription factor family, as a transforming growth factor-beta1 (TGF-beta1) responsive gene. We showed that TGF-beta1 upregulated transcription of FOXC1 in several human cancer cell lines. Ectopic expression of FOXC1 cDNA in HeLa cells, which lack both copies of the FOXC1 allele, restores the potential of TGF-beta1 to inhibit cell growth by arresting cells in the G0/G1 phase. In addition, screens of primary endometrial and ovarian cancers revealed homozygous deletion of FOXC1 in 6.7% of them, one nonsense and one missense mutation of FOXC1, and transcriptional silencing in 11.7% of primary cancers. Evidence that a significant fraction of primary cancers exhibited somatic mutations suggests that FOXC1 functions as a tumor suppressor through TGF-beta1 mediated signals.
Zhou
Yong
Y
Division of Molecular and Cell Therapeutics, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu, Oita, 874-0838, Japan.
Kato
Hidenori
H
Asanoma
Kazuo
K
Kondo
Haruhiko
H
Arima
Takahiro
T
Kato
Kiyoko
K
Matsuda
Takao
T
Wake
Norio
N
D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins; D016889:Endometrial Neoplasms / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D016153:Genes, Suppressor; D006367:HeLa Cells; D006801:Humans; D010051:Ovarian Neoplasms / Q000473:pathology; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D004268:DNA-Binding Proteins; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; C508960:TGFB1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1