The Transcription Factor FOXM1 (Forkhead box M1): Proliferation-Specific Expression, Transcription Factor Function, Target Genes, Mouse Models, and Normal Biological Roles

doi:10.1016/B978-0-12-407173-5.00004-2

Advances in Cancer Research

Volume 118, 2013, Pages 97-398

https://doi.org/10.1016/B978-0-12-407173-5.00004-2 Get rights and content

Abstract

FOXM1 (Forkhead box M1) is a typical proliferation-associated transcription factor, which stimulates cell proliferation and exhibits a proliferation-specific expression pattern. Accordingly, both the expression and the transcriptional activity of FOXM1 are increased by proliferation signals, but decreased by antiproliferation signals, including the positive and negative regulation by protooncoproteins or tumor suppressors, respectively. FOXM1 stimulates cell cycle progression by promoting the entry into S-phase and M-phase. Moreover, FOXM1 is required for proper execution of mitosis. Accordingly, FOXM1 regulates the expression of genes, whose products control G1/S-transition, S-phase progression, G2/M-transition, and M-phase progression. Additionally, FOXM1 target genes encode proteins with functions in the execution of DNA replication and mitosis. FOXM1 is a transcriptional activator with a forkhead domain as DNA binding domain and with a very strong acidic transactivation domain. However, wild-type FOXM1 is (almost) inactive because the transactivation domain is repressed by three inhibitory domains. Inactive FOXM1 can be converted into a very potent transactivator by activating signals, which release the transactivation domain from its inhibition by the inhibitory domains. FOXM1 is essential for embryonic development and the foxm1 knockout is embryonically lethal. In adults, FOXM1 is important for tissue repair after injury. FOXM1 prevents premature senescence and interferes with contact inhibition. FOXM1 plays a role for maintenance of stem cell pluripotency and for self-renewal capacity of stem cells. The functions of FOXM1 in prevention of polyploidy and aneuploidy and in homologous recombination repair of DNA-double-strand breaks suggest an importance of FOXM1 for the maintenance of genomic stability and chromosomal integrity.

Section snippets

FOXM1 is an Activating Transcription Factor

FOXM1 (Forkhead box M1) is a typical proliferation-associated transcription factor (Wierstra & Alves, 2007c) that is also intimately involved in oncogenesis (Costa, 2005, Costa et al., 2003, Costa et al., 2005, Kalin et al., 2011, Koo et al., 2011, Laoukili et al., 2007, Raychaudhuri and Park, 2011, Wierstra and Alves, 2007c). FOXM1 is an activating transcription factor (Fig. 3.1) with a very strong acidic TAD (transactivation domain) (Wierstra, 2013a, Wierstra and Alves, 2006a) and a forkhead

Four FOXM1 splice variants arise from differential splicing of three facultative exons in the foxm1 gene

Four different splice variants of FOXM1 have been described in mammals (human, mouse, rat) (Laoukili et al., 2007, Wierstra and Alves, 2007c), namely, FoxM1A, FoxM1B, FOXM1c, and rat WIN (class a transcript) (Fig. 3.1; Korver et al., 1997, Korver et al., 1997, Lüscher-Firzlaff et al., 1999, Yao et al., 1997, Ye et al., 1997).

Human FOXM1 is expressed in three distinct splice variants (Fig. 3.1), which arise from the same gene through differential splicing of the two facultative exons A1 and A2 (

Direct and possibly indirect FOXM1 target genes, which are regulated by FOXM1 at the transcript level

FOXM1 regulates the expression of over 220 genes (Fig. 3.2). It upregulates the mRNA expression of 199 protein-coding genes and downregulates the mRNA expression of 21 protein-coding genes (Fig. 3.2; Table 3.1). Additionally, FOXM1 upregulates the expression of one miRNA and downregulates the expression of five miRNAs (Fig. 3.2; Table 3.1).

Eighty genes are direct FOXM1 target genes, that is, FOXM1 was shown to associate with their promoters in ChIP (chromatin immunoprecipitation) assays, EMSAs,

Gene regulation mechanisms of FOXM1

FOXM1 is an activating transcription factor with a forkhead domain as DBD (Korver et al., 1997, Littler et al., 2010, Wierstra, 2011a, Wierstra and Alves, 2006a, Wierstra and Alves, 2006d, Yao et al., 1997, Ye et al., 1997) and with a very strong, acidic TAD (Wierstra, 2013a, Wierstra and Alves, 2006a). Since FOXM1 is a strong transactivator (Wierstra, 2013a, Wierstra and Alves, 2006a) it can transactivate the promoters of target genes as a classical (conventional) transcription factor by

The conventional transcription factor FOXM1

FOXM1 functions as a conventional transcription factor if it binds to a conventional FOXM1-binding site upstream (or downstream) of a non-FOXM1-responsive core promoter and transactivates the promoter through its very strong acidic TAD (Alvarez-Fernandez et al., 2011, Alvarez-Fernandez et al., 2010, Alvarez-Fernandez et al., 2010, Anders et al., 2011, Bhat et al., 2009a, Bhat et al., 2009b, Chen et al., 2009, Fu et al., 2008, Gemenetzidis et al., 2009, Grant et al., 2012, Kalinichenko et al.,

FOXM1 displays a proliferation-specific expression pattern

FOXM1 is a typical proliferation-associated transcription factor (Wierstra & Alves, 2007c). Accordingly, FOXM1 exhibits a strictly proliferation-specific expression pattern so that it is expressed in all proliferating cells but not in resting cells (Costa et al., 2003, Costa et al., 2001, Kalin et al., 2011, Koo et al., 2011, Laoukili et al., 2007, Murakami et al., 2010, Raychaudhuri and Park, 2011, Wierstra and Alves, 2007c).

FOXM1 is ubiquitously expressed in the developing embryo but its

General knockout of foxm1

The knockout of foxm1 in mice is embryonically lethal (Kim et al., 2005, Korver et al., 1998, Krupczak-Hollis et al., 2004, Ramakrishna et al., 2007) with defective development of heart (Bolte et al., 2011, Korver et al., 1998, Krupczak-Hollis et al., 2004, Ramakrishna et al., 2007), lung (Kalin et al., 2008, Kim et al., 2005, Ustiyan et al., 2009, Ustiyan et al., 2012) and liver (Krupczak-Hollis et al., 2004). Thus, FOXM1 is essential for embryonic development (Fig. 3.2; Kim et al., 2005,

Stimulation of cell proliferation

FOXM1 stimulates cell proliferation and promotes cell cycle progression at both the G1/S-transition and the G2/M-transition (Fig. 3.2; Costa, 2005, Costa et al., 2003, Costa et al., 2005, Costa et al., 2005, Kalin et al., 2011, Koo et al., 2011, Laoukili et al., 2007, Mackey et al., 2003, Myatt and Lam, 2007, Raychaudhuri and Park, 2011, Wierstra and Alves, 2007c). The stimulation of proliferation is one main function of FOXM1 and forms the basis of many of its biological roles (see below).

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Forkhead box (FOX) protein M1 (FOXM1) is a critical proliferation-associated transcription factor (TF) that is aberrantly overexpressed in the majority of human cancers and has also been implicated in poor prognosis. A comprehensive understanding of various aspects of this molecule has revealed its role in, cell proliferation, cell migration, invasion, angiogenesis and metastasis. The FOXM1 as a TF directly or indirectly regulates the expression of several target genes whose dysregulation is associated with almost all hallmarks of cancer. Moreover, FOXM1 expression is associated with chemoresistance to different anti-cancer drugs. Several studies have confirmed that suppression of FOXM1 enhanced the drug sensitivity of various types of cancer cells. Current data suggest that small molecule inhibitors targeting FOXM1 in combination with anticancer drugs may represent a novel therapeutic strategy for chemo-resistant cancers. In this review, we discuss the clinical utility of FOXM1, further, we summarize and discuss small-molecule inhibitors targeting FOXM1 and categorize them according to their mechanisms of targeting FOXM1. Despite great progress, small-molecule inhibitors targeting FOXM1 face many challenges, and we present here all small-molecule FOXM1 inhibitors in different stages of development. We discuss the current challenges and provide insights on the future application of FOXM1 inhibition to the clinic.
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2-Ethylhexyl diphenyl phosphate (EHDPP) is one of the typical organophosphate flame retardants (OPFRs) and has been widely detected in environmental media. Exposure to EHDPP during pregnancy affects placental development and fetal growth. Liver X receptor α (LXRα) is essential to placental development. However, finite information is available regarding the function of LXRα in placenta damages caused by EHDPP. In present study we investigated to figure out whether LXRα is playing roles in EHDPP-induced placenta toxicity. While EHDPP restrained cell viability, migration, and angiogenesis dose-dependently in HTR-8/SVneo and JEG-3 cells, overexpression or activation by agonist T0901317 of LXRα alleviated the above phenomenon, knockdown or inhibition by antagonist GSK2033 had the opposite effects in vitro. Further study indicated EHDPP decreased LXRα expression and transcriptional activity leading to mRNA, protein expression levels downregulation of viability, migration, angiogenesis-related genes Forkhead box M1 (Foxm1), endothelial nitric oxide synthase (eNos), matrix metalloproteinase-2 (Mmp-2), matrix metalloproteinase-9 (Mmp-9), vascular endothelial growth factor-A (Vegf-a) and upregulation of inﬂammatory genes interleukin-6 (Il-6), interleukin-1β (Il-1β) and tumor necrosis factor-α (Tnf-α) in vitro and in vivo. Moreover, EHDPP caused decreased placental volume and fetal weight in mice, treatment with LXRα agonist T0901317 restored these adverse effects. Taken together, our study unveiled EHDPP-induced placenta toxicity and the protective role of LXRα in combating EHDPP-induced placental dysfunction. Activating LXRα could serve as a therapeutic strategy to reverse EHDPP-induced placental toxicity.
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^*: The present chapter is Part I of a two-part review on the transcription factor FOXM1. Part II of this FOXM1 review is published in Volume 119 of Advances in Cancer Research: Inken Wierstra, FOXM1 (Forkhead box M1) in tumorigenesis: overexpression in human cancer, implication in tumorigenesis, oncogenic functions, tumor-suppressive properties and target of anti-cancer therapy. Advances in Cancer Research, 2013, Volume 119, in press.

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Chapter Three - The Transcription Factor FOXM1 (Forkhead box M1): Proliferation-Specific Expression, Transcription Factor Function, Target Genes, Mouse Models, and Normal Biological Roles*

Abstract

Section snippets

FOXM1 is an Activating Transcription Factor

Four FOXM1 splice variants arise from differential splicing of three facultative exons in the foxm1 gene

Direct and possibly indirect FOXM1 target genes, which are regulated by FOXM1 at the transcript level

Gene regulation mechanisms of FOXM1

The conventional transcription factor FOXM1

FOXM1 displays a proliferation-specific expression pattern

General knockout of foxm1

Stimulation of cell proliferation

Molecular Cell

DNA Repair

Molecular Cell

Journal of Biological Chemistry

Trends in Molecular Medicine

Biochimica et Biophysica Acta

Current Opinion in Genetics & Development

Progress in Molecular Biology and Translational Science

Cancer Cell

European Journal of Cancer

Current Opinion in Cell Biology

Cell

Developmental Biology

Immunity

Cancer Cell

Current Opinion in Cell Biology

Trends in Biochemical Sciences

The International Journal of Biochemistry & Cell Biology

FEBS Letters

Developmental Cell

Journal of Biological Chemistry

Journal of Biological Chemistry

Current Opinion in Genetics & Development

Current Biology

Journal of Biological Chemistry

Trends in Cell Biology

CRL4Cdt2: Master coordinator of cell cycle progression and genome stability

Cell Cycle

Cell cycle checkpoint signaling through the ATM and ATR kinases

Genes & Development

AKT signaling mediates IGF-I survival actions on otic neural progenitors

PLoS One

β-Cell proliferation, but not neogenesis, following 60% partial pancreatectomy is impaired in the absence of FoxM1

Diabetes

Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence

Cancer Research

Fibronectin inhibits the terminal differentiation of human keratinocytes

Nature

Changes in keratinocyte adhesion during terminal differentiation: Reduction in fibronectin binding precedes a5b1 integrin loss from the cell surface

Cell

DNA damage signaling in response to 5-fluorouracil in three colorectal cancer cell lines with different mismatch repair and TP53 status

International Journal of Oncology

Transcriptional regulation and transformation by Myc proteins

Nature Reviews. Molecular Cell Biology

Regulating the regulator: Post-translational modifications of RAS

Nature Reviews. Molecular Cell Biology

3,3′-Diindolylmethane enhances Taxotere-induced growth inhibition of breast cancer cells through down-regulation of FoxM1

International Journal of Cancer

FoxM1 down-regulation leads to inhibition of proliferation, migration and invasion of breast cancer cells through the modulation of extra-cellular matrix degrading factors

Breast Cancer Research and Treatment

FoxM1 and its association with matrix metalloproteinases (MMP) signaling pathway in papillary thyroid carcinoma

Journal of Clinical Endocrinology and Metabolism

Temporal expression changes during differentiation of neural stem cells derived from mouse embryonic stem cells

Journal of Cellular Biochemistry

SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation

Oncogene

Heat shock factors: Integrators of cell stress, development and life span

Nature Reviews. Molecular Cell Biology

Ts65Dn—Localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome

Cytogenetics and Cell Genetics

Cellular transformation by SV40 large T antigen: Interaction with host proteins

Seminars in Cancer Biology

Cell therapy for liver disease

Current Opinion in Molecular Therapeutics

Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer

Breast Cancer Research

Engineering liver therapies for the future

Tissue Engineering

Recovery from a DNA-damage-induced G2 arrest requires Cdk-dependent activation of FoxM1

CRL4^Cdt2: Master coordinator of cell cycle progression and genome stability

Computational identification of a p38^SAPK-regulated transcription factor network required for tumor cell quiescence