title: FOXP1 acts through a negative feedback loop to suppress FOXO-induced apoptosis.
abstract: Transcriptional activity of Forkhead box transcription factor class O (FOXO) proteins can result in a variety of cellular outcomes depending on cell type and activating stimulus. These transcription factors are negatively regulated by the phosphoinositol 3-kinase (PI3K)-protein kinase B (PKB) signaling pathway, which is thought to have a pivotal role in regulating survival of tumor cells in a variety of cancers. Recently, it has become clear that FOXO proteins can promote resistance to anti-cancer therapeutics, designed to inhibit PI3K-PKB activity, by inducing the expression of proteins that provide feedback at different levels of this pathway. We questioned whether such a feedback mechanism may also exist directly at the level of FOXO-induced transcription. To identify critical modulators of FOXO transcriptional output, we performed gene expression analyses after conditional activation of key components of the PI3K-PKB-FOXO signaling pathway and identified FOXP1 as a direct FOXO transcriptional target. Using chromatin immunoprecipitation followed by next-generation sequencing, we show that FOXP1 binds enhancers that are pre-occupied by FOXO3. By sequencing the transcriptomes of cells in which FOXO is specifically activated in the absence of FOXP1, we demonstrate that FOXP1 can modulate the expression of a specific subset of FOXO target genes, including inhibiting expression of the pro-apoptotic gene BIK. FOXO activation in FOXP1-knockdown cells resulted in increased cell death, demonstrating that FOXP1 prevents FOXO-induced apoptosis. We therefore propose that FOXP1 represents an important modulator of FOXO-induced transcription, promoting cellular survival.
authors.affiliation: Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van Boxtel
authors.forename: C
authors.initials: C
authors.lastname: Gomez-Puerto
authors.forename: M
authors.initials: M
authors.lastname: Mokry
authors.forename: A
authors.initials: A
authors.lastname: Eijkelenboom
authors.forename: K E
authors.initials: KE
authors.lastname: van der Vos
authors.forename: E E S
authors.initials: EE
authors.lastname: Nieuwenhuis
authors.forename: B M T
authors.initials: BM
authors.lastname: Burgering
authors.forename: E W-F
authors.initials: EW
authors.lastname: Lam
authors.forename: P J
authors.initials: PJ
authors.lastname: Coffer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D024101:Mitochondrial Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C111741:Bik protein, mouse; C467200:Foxo1 protein, mouse; C432917:Foxp1 protein, mouse