Increased expression of FoxM1 transcription factor in respiratory epithelium inhibits lung sacculation and causes Clara cell hyperplasia.
ABSTRACT Foxm1 is a member of the Forkhead Box (Fox) family of transcription factors. Foxm1 (previously called Foxm1b, HFH-11B, Trident, Win, or MPP2) is expressed in multiple cell types and plays important roles in cellular proliferation, differentiation and tumorigenesis. Genetic deletion of Foxm1 from mouse respiratory epithelium during initial stages of lung development inhibits lung maturation and causes respiratory failure after birth. However, the role of Foxm1 during postnatal lung morphogenesis remains unknown. In the present study, Foxm1 expression was detected in epithelial cells of conducting and peripheral airways and changing dynamically with lung maturation. To discern the biological role of Foxm1 in the prenatal and postnatal lung, a novel transgenic mouse line that expresses a constitutively active form of FoxM1 (FoxM1 N-terminal deletion mutant or FoxM1-ΔN) under the control of lung epithelial-specific SPC promoter was produced. Expression of the FoxM1-ΔN transgene during embryogenesis caused epithelial hyperplasia, inhibited lung sacculation and expression of the type II epithelial marker, pro-SPC. Expression of FoxM1-ΔN mutant during the postnatal period did not influence alveologenesis but caused focal airway hyperplasia and increased proliferation of Clara cells. Likewise, expression of FoxM1-ΔN mutant in conducting airways with Scgb1a1 promoter was sufficient to induce Clara cell hyperplasia. Furthermore, FoxM1-ΔN cooperated with activated K-Ras to induce lung tumor growth in vivo. Increased activity of Foxm1 altered lung sacculation, induced proliferation in the respiratory epithelium and accelerated lung tumor growth, indicating that precise regulation of Foxm1 is critical for normal lung morphogenesis and development of lung cancer.
Article: Myocardium defects and ventricular hypoplasia in mice homozygous null for the Forkhead Box M1 transcription factor.[show abstract] [hide abstract]
ABSTRACT: The Forkhead Box m1 (Foxm1) transcription factor is expressed in cardiomyocytes and cardiac endothelial cells during heart development. In this study, we used a novel Foxm1 -/- mouse line to demonstrate that Foxm1-deletion causes ventricular hypoplasia and diminished DNA replication and mitosis in developing cardiomyocytes. Proliferation defects in Foxm1 -/- hearts were associated with a reduced expression of Cdk1-activator Cdc25B phosphatase and NFATc3 transcription factor, and with abnormal nuclear accumulation of the Cdk-inhibitor p21(Cip1) protein. Depletion of Foxm1 levels by siRNA caused altered expression of these genes in cultured HL-1 cardiomyocytes. Endothelial-specific deletion of the Foxm1 fl/fl allele in Tie2-Cre Foxm1 fl/fl embryos did not influence heart development and cardiomyocyte proliferation. Foxm1 protein binds to the -9,259/-9,288-bp region of the endogenous mouse NFATc3 promoter, indicating that Foxm1 is a transcriptional activator of the NFATc3 gene. Foxm1 regulates expression of genes essential for the proliferation of cardiomyocytes during heart development.Developmental Dynamics 05/2007; 236(4):1000-13. · 2.54 Impact Factor
Article: beta-Catenin is required for specification of proximal/distal cell fate during lung morphogenesis.[show abstract] [hide abstract]
ABSTRACT: The lungs are divided, both structurally and functionally, into two distinct components, the proximal airways, which conduct air, and the peripheral airways, which mediate gas exchange. The mechanisms that control the specification of these two structures during lung development are currently unknown. Here we show that beta-catenin signaling is required for the formation of the distal, but not the proximal, airways. When the gene for beta-catenin was conditionally excised in epithelial cells of the developing mouse lung prior to embryonic day 14.5, the proximal lung tubules grew and differentiated appropriately. The mice, however, died at birth because of respiratory failure. Analysis of the lungs by in situ hybridization and immunohistochemistry, using molecular markers of the epithelial and mesenchymal components of both proximal and peripheral airways, showed that the lungs were composed primarily of proximal airways. These observations establish, for the first time, both the sites and timing of specification of the proximal and peripheral airways in the developing lung, and that beta-catenin is one of the essential components of this specification.Journal of Biological Chemistry 11/2003; 278(41):40231-8. · 4.77 Impact Factor
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ABSTRACT: Forkhead transcription factors are intimately involved in the regulation of organismal development, cell differentiation and proliferation. Here we review the current knowledge of the role played by FoxM1 in these various processes. This particular member of the Forkhead family is broadly expressed in actively dividing cells and is crucial for cell cycle-dependent gene expression in the G2 phase of the cell cycle. FoxM1 plays a crucial role in insuring the fidelity of the cell division process, as inhibition of FoxM1 activity results in serious aberrancies during mitosis, such as frequent chromosome missegregation, defects in cytokinesis and overt aneuploidy. FoxM1 expression also appears to be tightly correlated with the proliferative rate of a cell. For example, FoxM1 is one of the most significantly down-regulated genes in prematurely aged human fibroblasts (Progeria syndrome), while elevated expression of FoxM1 is seen in most human carcinomas. These observations suggest that interference with FoxM1 activity may contribute to the increase in mitotic errors seen in human diseases such as cancer and early onset of ageing diseases. In this review, several aspects of FoxM1 function will be discussed, as well as their implication in tumorigenesis.Biochimica et Biophysica Acta 02/2007; 1775(1):92-102. · 4.66 Impact Factor