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Sox17 promotes cell cycle progression and inhibits TGF-beta/Smad3 signaling to initiate progenitor cell behavior in the respiratory epithelium.

Lange AW, Keiser AR, Wells JM, Zorn AM, Whitsett JA - PLoS ONE (2009)

Bottom Line: Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro.Sox17 decreased the expression of transforming growth factor-beta (TGF-beta)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-beta1-mediated transcriptional responses in vitro.Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

ABSTRACT
The Sry-related high mobility group box transcription factor Sox17 is required for diverse developmental processes including endoderm formation, vascular development, and fetal hematopoietic stem cell maintenance. Expression of Sox17 in mature respiratory epithelial cells causes proliferation and lineage respecification, suggesting that Sox17 can alter adult lung progenitor cell fate. In this paper, we identify mechanisms by which Sox17 influences lung epithelial progenitor cell behavior and reprograms cell fate in the mature respiratory epithelium. Conditional expression of Sox17 in epithelial cells of the adult mouse lung demonstrated that cell cluster formation and respecification of alveolar progenitor cells toward proximal airway lineages were rapidly reversible processes. Prolonged expression of Sox17 caused the ectopic formation of bronchiolar-like structures with diverse respiratory epithelial cell characteristics in alveolar regions of lung. During initiation of progenitor cell behavior, Sox17 induced proliferation and increased the expression of the progenitor cell marker Sca-1 and genes involved in cell cycle progression. Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro. Sox17 decreased the expression of transforming growth factor-beta (TGF-beta)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-beta1-mediated transcriptional responses in vitro. Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity. Together, these data show that a subset of mature respiratory epithelial cells retains remarkable phenotypic plasticity and that Sox17, a gene required for early endoderm formation, activates the cell cycle and reinitiates multipotent progenitor cell behavior in mature lung cells.

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Sox17 regulates genes that control the cell cycle.RT-PCR was used to assess expression of cell cycle-related genes in lung tissue from adult CCSPrtTA and CCSPrtTA/tetO-Sox17 mice treated with Dox for 1 or 3 days. Transcripts for the cyclin-dependent kinase inhibitors p15, p21, and p57 were decreased in Sox17 transgenic lungs after 1 day of Dox and mRNAs for genes associated with cell cycle progression were increased by Sox17 after 3 days Dox exposure. L7 was used as a loading control.
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pone-0005711-g005: Sox17 regulates genes that control the cell cycle.RT-PCR was used to assess expression of cell cycle-related genes in lung tissue from adult CCSPrtTA and CCSPrtTA/tetO-Sox17 mice treated with Dox for 1 or 3 days. Transcripts for the cyclin-dependent kinase inhibitors p15, p21, and p57 were decreased in Sox17 transgenic lungs after 1 day of Dox and mRNAs for genes associated with cell cycle progression were increased by Sox17 after 3 days Dox exposure. L7 was used as a loading control.

Mentions: Since expression of Sox17 in respiratory epithelial cells in the adult mouse lung induced cell proliferation, the effects on cell cycle-associated gene expression was examined to identify potential downstream targets of Sox17 that regulate this process. Total RNA isolated from whole left lobes of adult CCSPrtTA control and CCSPrtTA/tetO-Sox17 mice maintained on Dox for 2 and 3 days was used to analyze changes in cell cycle-related gene expression with a commercially available oligo SuperArray (data not shown). Subsequently, RT-PCR was used to confirm the changes in expression of a subset of the genes identified in the array. In addition to increased expression of Sox17 (data not shown), mRNAs for the cyclin-dependent kinase inhibitors p15, p21, and p57 were significantly decreased in lungs of CCSPrtTA/tetO-Sox17 mice relative to CCSPrtTA controls following 1 day of exposure to Dox (Fig. 5). Whereas expression of p57 was also decreased on lungs from CCSPrtTA/tetO-Sox17 mice maintained on Dox for 3 days, expression of p15 and p21 was similar to controls. Further, while expression of p19 was variably decreased in lungs from CCSPrtTA/tetO-Sox17 mice maintained on Dox for 2 days, no differences in the expression of p16 or p27 were observed after expression of Sox17 for 1–3 days (data not shown). Consistent with the induction of proliferation observed by immunohistochemistry (Fig. 3), transcripts for genes that promote cell cycle progression, including Foxm1, cyclin A2, cyclin B1, cyclin D1, and cyclin E1, were increased in lungs of CCSPrtTA/tetO-Sox17 mice after 3 days of Dox treatment (Fig. 5). Together, these results demonstrate that Sox17 expression in adult mouse lung results in decreased levels of cyclin-dependent kinase inhibitors associated with G1 arrest and increased expression of cell cycle-promoting genes, providing insight into the molecular mechanisms that regulate Sox17-induced proliferation associated with the initiation of progenitor cell behavior in respiratory epithelial cells.


Sox17 promotes cell cycle progression and inhibits TGF-beta/Smad3 signaling to initiate progenitor cell behavior in the respiratory epithelium.

Lange AW, Keiser AR, Wells JM, Zorn AM, Whitsett JA - PLoS ONE (2009)

Sox17 regulates genes that control the cell cycle.RT-PCR was used to assess expression of cell cycle-related genes in lung tissue from adult CCSPrtTA and CCSPrtTA/tetO-Sox17 mice treated with Dox for 1 or 3 days. Transcripts for the cyclin-dependent kinase inhibitors p15, p21, and p57 were decreased in Sox17 transgenic lungs after 1 day of Dox and mRNAs for genes associated with cell cycle progression were increased by Sox17 after 3 days Dox exposure. L7 was used as a loading control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682659&req=5

pone-0005711-g005: Sox17 regulates genes that control the cell cycle.RT-PCR was used to assess expression of cell cycle-related genes in lung tissue from adult CCSPrtTA and CCSPrtTA/tetO-Sox17 mice treated with Dox for 1 or 3 days. Transcripts for the cyclin-dependent kinase inhibitors p15, p21, and p57 were decreased in Sox17 transgenic lungs after 1 day of Dox and mRNAs for genes associated with cell cycle progression were increased by Sox17 after 3 days Dox exposure. L7 was used as a loading control.
Mentions: Since expression of Sox17 in respiratory epithelial cells in the adult mouse lung induced cell proliferation, the effects on cell cycle-associated gene expression was examined to identify potential downstream targets of Sox17 that regulate this process. Total RNA isolated from whole left lobes of adult CCSPrtTA control and CCSPrtTA/tetO-Sox17 mice maintained on Dox for 2 and 3 days was used to analyze changes in cell cycle-related gene expression with a commercially available oligo SuperArray (data not shown). Subsequently, RT-PCR was used to confirm the changes in expression of a subset of the genes identified in the array. In addition to increased expression of Sox17 (data not shown), mRNAs for the cyclin-dependent kinase inhibitors p15, p21, and p57 were significantly decreased in lungs of CCSPrtTA/tetO-Sox17 mice relative to CCSPrtTA controls following 1 day of exposure to Dox (Fig. 5). Whereas expression of p57 was also decreased on lungs from CCSPrtTA/tetO-Sox17 mice maintained on Dox for 3 days, expression of p15 and p21 was similar to controls. Further, while expression of p19 was variably decreased in lungs from CCSPrtTA/tetO-Sox17 mice maintained on Dox for 2 days, no differences in the expression of p16 or p27 were observed after expression of Sox17 for 1–3 days (data not shown). Consistent with the induction of proliferation observed by immunohistochemistry (Fig. 3), transcripts for genes that promote cell cycle progression, including Foxm1, cyclin A2, cyclin B1, cyclin D1, and cyclin E1, were increased in lungs of CCSPrtTA/tetO-Sox17 mice after 3 days of Dox treatment (Fig. 5). Together, these results demonstrate that Sox17 expression in adult mouse lung results in decreased levels of cyclin-dependent kinase inhibitors associated with G1 arrest and increased expression of cell cycle-promoting genes, providing insight into the molecular mechanisms that regulate Sox17-induced proliferation associated with the initiation of progenitor cell behavior in respiratory epithelial cells.

Bottom Line: Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro.Sox17 decreased the expression of transforming growth factor-beta (TGF-beta)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-beta1-mediated transcriptional responses in vitro.Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

ABSTRACT
The Sry-related high mobility group box transcription factor Sox17 is required for diverse developmental processes including endoderm formation, vascular development, and fetal hematopoietic stem cell maintenance. Expression of Sox17 in mature respiratory epithelial cells causes proliferation and lineage respecification, suggesting that Sox17 can alter adult lung progenitor cell fate. In this paper, we identify mechanisms by which Sox17 influences lung epithelial progenitor cell behavior and reprograms cell fate in the mature respiratory epithelium. Conditional expression of Sox17 in epithelial cells of the adult mouse lung demonstrated that cell cluster formation and respecification of alveolar progenitor cells toward proximal airway lineages were rapidly reversible processes. Prolonged expression of Sox17 caused the ectopic formation of bronchiolar-like structures with diverse respiratory epithelial cell characteristics in alveolar regions of lung. During initiation of progenitor cell behavior, Sox17 induced proliferation and increased the expression of the progenitor cell marker Sca-1 and genes involved in cell cycle progression. Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro. Sox17 decreased the expression of transforming growth factor-beta (TGF-beta)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-beta1-mediated transcriptional responses in vitro. Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity. Together, these data show that a subset of mature respiratory epithelial cells retains remarkable phenotypic plasticity and that Sox17, a gene required for early endoderm formation, activates the cell cycle and reinitiates multipotent progenitor cell behavior in mature lung cells.

Show MeSH
Related in: MedlinePlus