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Wang, X., Kiyokawa, H., Dennewitz, M. B. & Costa, R. H. The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration. Proc. Natl Acad. Sci. USA 99, 16881-16886

University of Illinois at Chicago, Chicago, Illinois, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2003; 99(26):16881-6. DOI: 10.1073/pnas.252570299
Source: PubMed

ABSTRACT

The Forkhead Box (Fox) proteins are an extensive family of transcription factors that shares homology in the winged helix DNA-binding domain and whose members play essential roles in cellular proliferation, differentiation, transformation, longevity, and metabolic homeostasis. Liver regeneration studies with transgenic mice demonstrated that FoxM1B regulates the onset of hepatocyte DNA replication and mitosis by stimulating expression of cell cycle genes. Here, we demonstrate that albumin-promoter-driven Cre recombinase-mediated hepatocyte-specific deletion of the Foxm1b Floxed (fl) targeted allele resulted in significant reduction in hepatocyte DNA replication and inhibition of mitosis after partial hepatectomy. Reduced DNA replication in regenerating Foxm1b(-/-) hepatocytes was associated with sustained increase in nuclear staining of the cyclin-dependent kinase (Cdk) inhibitor p21(Cip1) (p21) protein between 24 and 40 h after partial hepatectomy. Furthermore, increased nuclear p21 levels and reduced expression of Cdc25A phosphatase coincided with decreases in Cdk2 activation and hepatocyte progression into S-phase. Moreover, the significant reduction in hepatocyte mitosis was associated with diminished mRNA levels and nuclear expression of Cdc25B phosphatase and delayed accumulation of cyclin B1 protein, which is required for Cdk1 activation and entry into mitosis. Cotransfection studies demonstrate that FoxM1B protein directly activated transcription of the Cdc25B promoter region. Our present study shows that the mammalian Foxm1b transcription factor regulates expression of cell cycle proteins essential for hepatocyte entry into DNA replication and mitosis.

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Available from: Xinhe Wang, Apr 14, 2014
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    • "It is activated by mammalian mitotic kinase Pololike kinase-1 (Plk1) through binding to carboxyl terminal domain of FOXM1 and through further phosphorylation of two residues on this domain by cyclin-dependent kinase 1 (Cdk1)[15], cyclin E-CDK2[16], and Raf-MEK-ERKmediated phosphorylation[14]. FoxM1 has been shown to regulate the transcription of genes involved in cell cycle by binding to promoter of cyclin D1 and cyclin B1 genes[17]and by direct activation of transcription of the Cdc25B phosphatase promoter region[18]. In the hepatoblasts of Foxm1b −/− murine embryos mitosis was associated with decreased expression of the Aurora B kinase and Polo-like kinase 1 (Plk1) and Cdc25A phosphatase[19].Wang et al.showed, using quantitative chromatin immunoprecipitation and expression, that FoxM1 is necessary for transcription of the Aurora B kinase, survivin, centromere protein A (CENPA), and CENPB[20]. "
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    ABSTRACT: The Forkhead box M1 (FOXM1) is a transcription factor that has been implicated in normal cell growth and proliferation through control of cell cycle transition and mitotic spindle. It is implicated in carcinogenesis of various malignancies where it is activated by either amplification, increased stability, enhanced transcription, dysfunction of regulatory pathways, or activation of PI3K/AKT, epidermal growth factor receptor, Raf/MEK/MAPK, and Hedgehog pathways. This review describes the role of FOXM1 in breast cancer. This includes how FOXM1 impacts on different subtypes of breast cancer, that is, luminal/estrogen receptor positive (ER+), expressing human epidermal growth factor receptor 2 (HER2), basal-like breast cancer (BBC), and triple negative breast cancer (TNBC). The review also describes different tested preclinical therapeutic strategies targeting FOXM1. Developing clinically applicable therapies that specifically inhibit FOXM1 activity is a logical next step in biomarker-driven approaches against breast cancer but will not be without its challenges due to the unique properties of this transcription factor.
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    • "RA-mediated activation of Foxm1 facilitates a coordinated induction of several common target genes through RARb binding. Foxm1 also regulates Cdc25, Cyclin E/Cdk2, and Cyclin B/Cdk1, making it a critical gatekeeper of G1/S and G2/ M cell cycle transitions, as well as mitotic spindle assembly [39]. The E2f transcription factor family plays an important role in regulating cellular proliferation by activating a panel of genes involved in progression through the G1 phase as well as DNA replication [23]. "
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    ABSTRACT: All-trans retinoic acid (RA) is a potent inducer of regeneration. Because the liver is the principal site for storage and bioactivation of vitamin A, the current study examines the effect of RA in mouse hepatocyte proliferation and liver regeneration. Mice that received a single dose of RA (25μg/g) by oral gavage developed hepatomegaly with increased number of Ki67-positive cells and induced expression of cell cycle genes in the liver. DNA binding data revealed that RA receptors retinoic acid receptor β (RARβ) and retinoid x receptor α (RXRα) bound to cell cycle genes Cdk1, Cdk2, Cyclin B, Cyclin E, and Cdc25a in mice with and without RA treatment. In addition, RA treatment induced novel binding of RARβ/RXRα to Cdk1, Cdk2, Cyclin D, and Cdk6 genes. All RARβ/RXRα binding sites contained AGGTCA-like motifs. RA treatment also promoted liver regeneration after partial hepatectomy (PH). RA signaling was implicated in normal liver regeneration as the mRNA levels of RARβ, Aldh1a2, Crabp1, and Crbp1 were all induced 1.5 days after PH during the active phase of hepatocyte proliferation. RA treatment prior to PH resulted in early up-regulation of RARβ, Aldh1a2, Crabp1, and Crbp1, which was accompanied by an early induction of cell cycle genes. Western blotting for RARβ, c-myc, Cyclin D, E, and A further supported the early induction of retinoid signal and cell proliferation by RA treatment. Taken together, our data suggest that RA may regulate cell cycle progression and accelerates liver regeneration. Such effect is associated with an early induction of RA signaling, which includes increased expression of the receptor, binding proteins, and processing enzyme for retinoids.
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    • "RA-mediated activation of Foxm1 facilitates a coordinated induction of several common target genes through RARb binding. Foxm1 also regulates Cdc25, Cyclin E/Cdk2, and Cyclin B/Cdk1, making it a critical gatekeeper of G1/S and G2/ M cell cycle transitions, as well as mitotic spindle assembly [39]. The E2f transcription factor family plays an important role in regulating cellular proliferation by activating a panel of genes involved in progression through the G1 phase as well as DNA replication [23]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: All-trans retinoic acid (RA) is a potent inducer of regeneration. Because the liver is the principal site for storage and bioactivation of vitamin A, the current study examines the effect of RA in mouse hepatocyte proliferation and liver regeneration. Mice that received a single dose of RA (25μg/g) by oral gavage developed hepatomegaly with increased number of Ki67-positive cells and induced expression of cell cycle genes in the liver. DNA binding data revealed that RA receptors retinoic acid receptor β (RARβ) and retinoid x receptor α (RXRα) bound to cell cycle genes Cdk1, Cdk2, Cyclin B, Cyclin E, and Cdc25a in mice with and without RA treatment. In addition, RA treatment induced novel binding of RARβ/RXRα to Cdk1, Cdk2, Cyclin D, and Cdk6 genes. All RARβ/RXRα binding sites contained AGGTCA-like motifs. RA treatment also promoted liver regeneration after partial hepatectomy (PH). RA signaling was implicated in normal liver regeneration as the mRNA levels of RARβ, Aldh1a2, Crabp1, and Crbp1 were all induced 1.5 days after PH during the active phase of hepatocyte proliferation. RA treatment prior to PH resulted in early up-regulation of RARβ, Aldh1a2, Crabp1, and Crbp1, which was accompanied by an early induction of cell cycle genes. Western blotting for RARβ, c-myc, Cyclin D, E, and A further supported the early induction of retinoid signal and cell proliferation by RA treatment. Taken together, our data suggest that RA may regulate cell cycle progression and accelerates liver regeneration. Such effect is associated with an early induction of RA signaling, which includes increased expression of the receptor, binding proteins, and processing enzyme for retinoids.
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