title: The LIM-domain only protein 4 contributes to lung epithelial cell proliferation but is not essential for tumor progression.
abstract: BACKGROUND
  The lung is constantly exposed to environmental challenges and must rapidly respond to external insults. Mechanisms involved in the repair of the damaged lung involve expansion of different epithelial cells to repopulate the injured cellular compartment. However, factors regulating cell proliferation following lung injury remain poorly understood. Here we studied the role of the transcriptional regulator Lmo4 during lung development, in the regulation of adult lung epithelial cell proliferation following lung damage and in the context of oncogenic transformation.
  
  
  METHODS
  To study the role of Lmo4 in embryonic lung development, lung repair and tumorigenesis, we used conditional knock-out mice to delete Lmo4 in lung epithelial cells from the first stages of lung development. The role of Lmo4 in lung repair was evaluated using two experimental models of lung damage involving chemical and viral injury. The role of Lmo4 in lung tumorigenesis was measured using a mouse model of lung adenocarcinoma in which the oncogenic K-Ras protein has been knocked into the K-Ras locus. Overall survival difference between genotypes was tested by log rank test. Difference between means was tested using one-way ANOVA after assuring that assumptions of normality and equality of variance were satisfied.
  
  
  RESULTS
  We found that Lmo4 was not required for normal embryonic lung morphogenesis. In the adult lung, loss of Lmo4 reduced epithelial cell proliferation and delayed repair of the lung following naphthalene or flu-mediated injury, suggesting that Lmo4 participates in the regulation of epithelial cell expansion in response to cellular damage. In the context of K-Ras(G12D)-driven lung tumor formation, Lmo4 loss did not alter overall survival but delayed initiation of lung hyperplasia in K-Ras(G12D) mice sensitized by naphthalene injury. Finally, we evaluated the expression of LMO4 in tissue microarrays of early stage non-small cell lung cancer and observed that LMO4 is more highly expressed in lung squamous cell carcinoma compared to adenocarcinoma.
  
  
  CONCLUSIONS
  Together these results show that the transcriptional regulator Lmo4 participates in the regulation of lung epithelial cell proliferation in the context of injury and oncogenic transformation but that Lmo4 depletion is not sufficient to prevent lung repair or tumour formation.
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. holik.a@wehi.edu.au.|Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. holik.a@wehi.edu.au.
authors.forename: Aliaksei Z
authors.initials: AZ
authors.lastname: Holik
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. caitlin.filby@yahoo.com.au.|Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. caitlin.filby@yahoo.com.au.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Filby
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. pasquet.j@wehi.edu.au.
authors.forename: Julie
authors.initials: J
authors.lastname: Pasquet
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. kati.m.viitaniemi@gmail.com.
authors.forename: Kati
authors.initials: K
authors.lastname: Viitaniemi
authors.affiliation: The Alfred Hospital, Melbourne, VIC, Australia. jciciulla@gmail.com.
authors.forename: John
authors.initials: J
authors.lastname: Ciciulla
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. sutherland.k@wehi.edu.au.|Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. sutherland.k@wehi.edu.au.
authors.forename: Kate D
authors.initials: KD
authors.lastname: Sutherland
authors.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. labat@wehi.edu.au.|Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. labat@wehi.edu.au.
authors.forename: Marie-Liesse
authors.initials: ML
authors.lastname: Asselin-Labat
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency*; D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D018450:Disease Progression; D006801:Humans; D060588:LIM Domain Proteins / Q000172:deficiency*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; C114905:LMO4 protein, human