Compensatory Roles of Foxa1 and Foxa2 during Lung Morphogenesis

Wan, Hang; Dingle, Sharon; Xu, Yan; Besnard, Valérie; Kaestner, Klaus H.; Ang, Siew‐Lan; Wert, Susan E.; Stahlman, Mildred T.; Whitsett, Jeffrey A.

doi:10.1074/jbc.m414122200

Cited by 253 publications

(235 citation statements)

References 57 publications

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“…IL-13 and EGFR signaling can also downregulate Foxa2. Some evidence indicates that Foxa2 can promote Clara cell formation (115). These data are consistent with the above data regarding the ability of Clara cells to transdifferentiate into mucous cells, and Foxa2 may be the key transcription factor that modulates this process.…”

Section: Negative Regulators Of Muc5ac Expression and Of Mucous Cellsupporting

confidence: 80%

Regulation of Airway Mucin Gene Expression

Thai

Loukoianov

Wachi

et al. 2008

Annu. Rev. Physiol.

193

223

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Mucins are important components that exert a variety of functions in cell-cell interaction, epidermal growth factor receptor signaling, and airways protection. In the conducting airways of the lungs, mucins are the major contributor to the viscoelastic property of mucous secretion, which is the major barrier to trapping inhaled microbial organism, particulates, and oxidative pollutants. The homeostasis of mucin production is an important feature in conducting airways for the maintenance of mucociliary function. Aberrant mucin secretion and accumulation in airway lumen are clinical hallmarks associated with various lung diseases, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, emphysema, and lung cancer. Among 20 known mucin genes identified, 11 of them have been verified at either the mRNA and/or protein level in airways. The regulation of mucin genes is complicated, as are the mediators and signaling pathways. This review summarizes the current view on the mediators, the signaling pathways, and the transcriptional units that are involved in the regulation of airway mucin gene expression. In addition, we also point out essential features of epigenetic mechanisms for the regulation of these genes.

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Section: Negative Regulators Of Muc5ac Expression and Of Mucous Cellsupporting

confidence: 80%

Regulation of Airway Mucin Gene Expression

Thai

Loukoianov

Wachi

et al. 2008

Annu. Rev. Physiol.

193

223

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“…FOXA1 contributes to pancreatic beta-cell function 32 and both regulate signaling and transcriptional programs required for morphogenesis and goblet cell differentiation during formation. 33,34 There is a binding site for Hepatic Nuclear Factor 1 (HNF1) in the AGR2 promoter region at SNP 07AGRNP53. HNF1 and FOXA1 and FOXA2 belong to the same family.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease

Rosenstiel²,

Huse³

et al. 2005

Genes Immun

119

117

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Linkage analyses have implicated chromosome 7p21.3 as a susceptibility region for inflammatory bowel disease (IBD). Recently, the mouse phenotype with diarrhea and goblet cell dysfunction caused by anterior gradient protein 2 dysfunction was reported (European patent WO2004056858). The genes encoding for the human homologues AGR2 and AGR3 are localized on chromosome 7p21.3. The gene structures were verified and mutation detection was performed in 47 IBD patients. A total of 30 single nucleotide polymorphisms (SNPs) were tested for association to ulcerative colitis (UC, N ¼ 317) and Crohn's disease (CD, N ¼ 631) in a German cohort and verified in a UK cohort of 384 CD and 311 UC patients. An association signal was identified in the 5 0 region of the AGR2 gene (most significant SNP hcv1702494, nominal P TDT ¼ 0.011, P case/control ¼ 0.0007, OR ¼ 1.34, combined cohort). The risk haplotype carried an odds ratio of 1.43 in the German population (P ¼ 0.002). AGR2 was downregulated in UC patients as compared to normal controls (Po0.001) and a trend toward lower expression was seen in carriers of the risk alleles. Luciferase assays of the AGR2 promoter showed regulation by the goblet cell-specific transcription factors FOXA1 and FOXA2. In summary, AGR2 represents an interesting new avenue into the etiopathophysiology of IBD and the maintenance of epithelial integrity.

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“…All three transcription factors in this study are well-established developmental regulators. Nkx2-1 and Foxa2 are important developmental regulators of the lungs as well as other endoderm-derived organs (Kimura et al 1996;Zhou et al 1997;Minoo et al 1999;Wan et al 2005). Nkx2-1 is a homeodomain-containing transcription factor essential for differentiation of the lungs during early embryogenesis (Kimura et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis

Gocheva

Oudin

et al. 2015

Genes Dev.

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Despite the fact that the majority of lung cancer deaths are due to metastasis, the molecular mechanisms driving metastatic progression are poorly understood. Here, we present evidence that loss of Foxa2 and Cdx2 synergizes with loss of Nkx2-1 to fully activate the metastatic program. These three lineage-specific transcription factors are consistently down-regulated in metastatic cells compared with nonmetastatic cells. Knockdown of these three factors acts synergistically and is sufficient to promote the metastatic potential of nonmetastatic cells to that of naturally arising metastatic cells in vivo. Furthermore, silencing of these three transcription factors is sufficient to account for a significant fraction of the gene expression differences between the nonmetastatic and metastatic states in lung adenocarcinoma, including up-regulated expression of the invadopodia component Tks5 long , the embryonal protooncogene Hmga2, and the epithelial-to-mesenchymal mediator Snail. Finally, analyses of tumors from a genetically engineered mouse model and patients show that low expression of Nkx2-1, Foxa2, and Cdx2 strongly correlates with more advanced tumors and worse survival. Our findings reveal that a large part of the complex transcriptional network in metastasis can be controlled by a small number of regulatory nodes that function redundantly, and loss of multiple nodes is required to fully activate the metastatic program.[Keywords: lung adenocarcinoma; metastasis; Nkx2-1; Foxa2; Cdx2; genetically engineered mouse model of cancer] Supplemental material is available for this article.

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Compensatory Roles of Foxa1 and Foxa2 during Lung Morphogenesis

Cited by 253 publications

References 57 publications

Regulation of Airway Mucin Gene Expression

Regulation of Airway Mucin Gene Expression

Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease

Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis

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