Increased expression of FoxM1 transcription factor in respiratory epithelium inhibits lung sacculation and causes Clara cell hyperplasia.
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.
Wang
I-Ching
IC
Division of Pulmonary Biology, Perinatal Institute of the Cincinnati Children's Hospital Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229, USA. I-Ching.Wang@cchmc.org
Zhang
Yufang
Y
Snyder
Jonathan
J
Sutherland
Mardi J
MJ
Burhans
Michael S
MS
Shannon
John M
JM
Park
Hyun Jung
HJ
Whitsett
Jeffrey A
JA
Kalinichenko
Vladimir V
VV
D000818:Animals; D049108:Cell Enlargement; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D011905:Genes, ras; D006801:Humans; D006965:Hyperplasia; D008168:Lung / Q000166:cytology / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D020545:Respiratory Mucosa / Q000166:cytology / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism
D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D050505:Mutant Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins
Transgenic Res. 2002 Feb;11(1):21-9
11874100
Dev Biol. 2009 Dec 15;336(2):266-79
19835856
Mol Cell Biol. 2008 Sep;28(17):5162-71
18573889
Cancer Cell. 2004 Apr;5(4):375-87
15093544
Development. 2004 Feb;131(4):953-64
14757645
Oncogene. 2008 Mar 13;27(12):1696-704
17891172
Mol Cell Biol. 1997 Mar;17(3):1626-41
9032290
Hepatology. 2003 Dec;38(6):1331-47
14647040
Nat Cell Biol. 2005 Feb;7(2):108-10
15689977
Mol Cell Biol. 2007 Dec;27(23):8259-70
17893320
Dev Dyn. 2007 Apr;236(4):1000-13
17366632
Curr Biol. 1998 Dec 3;8(24):1327-30
9843684
Dev Biol. 2002 Feb 15;242(2):75-87
11820807
Am J Physiol Lung Cell Mol Physiol. 2002 Aug;283(2):L468-75
12114210
Am J Respir Cell Mol Biol. 2008 Mar;38(3):337-45
17921358
Biochim Biophys Acta. 2007 Jan;1775(1):92-102
17014965
J Biol Chem. 2003 Oct 10;278(41):40231-8
12885771
Cancer Res. 2005 Jun 15;65(12):5181-9
15958562
Hum Pathol. 2009 Apr;40(4):464-70
19121844
J Biol Chem. 2003 Jan 3;278(1):415-21
12399466
Development. 2008 Jun;135(11):2023-30
18469223
Oncogene. 2008 Jul 10;27(30):4137-49
18345025
Mol Cell Biol. 2004 Apr;24(7):2649-61
15024056
Dev Biol. 2006 Jun 1;294(1):192-202
16574095
J Clin Invest. 2009 Oct;119(10):2914-24
19759516
Mol Cell Biol. 2008 May;28(9):3076-87
18285455
Genes Dev. 2007 Mar 15;21(6):694-707
17369402
Gastroenterology. 2007 Apr;132(4):1420-31
17408638
Nature. 2001 Apr 26;410(6832):1111-6
11323676
Mol Cell Biol. 2005 Dec;25(24):10875-94
16314512
Am J Respir Cell Mol Biol. 1999 Aug;21(2):168-76
10423398
Mol Endocrinol. 2006 Aug;20(8):1853-66
16556734
Cancer Res. 2006 Feb 15;66(4):2153-61
16489016
Hepatology. 2008 Oct;48(4):1302-11
18798339
Dev Biol. 2004 Dec 1;276(1):74-88
15531365
Am J Physiol Lung Cell Mol Physiol. 2001 Apr;280(4):L705-15
11238011
J Cell Biochem. 2009 Feb 1;106(2):247-56
19097132
J Biol Chem. 2008 Jul 25;283(30):20770-8
18524773
J Biol Chem. 2005 Jun 10;280(23):22278-86
15817462
Lung Cancer. 2009 Oct;66(1):64-74
19200615
Science. 1995 Jun 23;268(5218):1766-9
7792603
J Clin Invest. 2006 Oct;116(10):2597-609
16998587
J Histochem Cytochem. 1999 Jun;47(6):823-32
10330459
Genes Dev. 2004 Apr 1;18(7):830-50
15082532
PLoS One. 2009 Aug 12;4(8):e6609
19672312
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19330-5
19033457
Development. 2008 Mar;135(6):1049-58
18256198
Toxicol Pathol. 1996 Nov-Dec;24(6):710-6
8994298
Clin Genet. 1999 Jul;56(1):14-27
10466413
J Biol Chem. 2003 Sep 26;278(39):37888-94
12867420
J Cell Sci. 2005 Feb 15;118(Pt 4):795-806
15671063
PLoS One. 2009 Dec 14;4(12):e8248
20011520
J Biol Chem. 2000 Apr 21;275(16):11858-64
10766812
Nature. 2004 Nov 18;432(7015):298-306
15549091
Mech Dev. 2000 Mar 15;92(1):55-81
10704888
Genes Dev. 2001 Dec 15;15(24):3249-62
11751631
Cancer Res. 2002 Aug 15;62(16):4773-80
12183437
Cancer Res. 2006 Feb 1;66(3):1712-20
16452231