title: The EGF receptor ligand amphiregulin controls cell division via FoxM1.
abstract: Epidermal growth factor receptor (EGFR) is central to epithelial cell physiology, and deregulated EGFR signaling has an important role in a variety of human carcinomas. Here we show that silencing of the EGF-related factor amphiregulin (AREG) markedly inhibits the expansion of human keratinocytes through mitotic failure and accumulation of cells with ⩾ 4n DNA content. RNA-sequencing-based transcriptome analysis revealed that tetracycline-mediated AREG silencing significantly altered the expression of 2331 genes, 623 of which were not normalized by treatment with EGF. Interestingly, genes irreversibly upregulated by suppression of AREG overlapped with genes involved in keratinocyte differentiation. Moreover, a significant proportion of the irreversibly downregulated genes featured upstream binding sites recognized by forkhead box protein M1 (FoxM1), a key transcription factor in the control of mitosis that is widely dysregulated in cancer. The downregulation of FoxM1 and its target genes preceded mitotic arrest. Constitutive expression of FoxM1 in AREG knockdown cells normalized cell proliferation, reduced the number of cells with ⩾ 4n DNA content and rescued expression of FoxM1 target genes. These results demonstrate that AREG controls G2/M progression and cytokinesis in keratinocytes via activation of a FoxM1-dependent transcriptional program, suggesting new avenues for treatment of epithelial cancer.
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Stoll
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: P E
authors.initials: PE
authors.lastname: Stuart
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: Swindell
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Tsoi
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gandarillas
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lambert
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: A
authors.initials: A
authors.lastname: Johnston
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Nair
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.|Ann Arbor Veterans Affairs Health System, Ann Arbor, MI, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Elder
mesh_terms: D066258:Amphiregulin; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D066255:EGF Family of Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D016195:G2 Phase; D020868:Gene Silencing; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008024:Ligands
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D008024:Ligands; D066246:ErbB Receptors