title: Reduced expression level of the cyclic adenosine monophosphate response element-binding protein contributes to lung aging.
abstract: Lung aging is associated with morphological and physiological changes in which alterations in transcription factors, including the cyclic adenosine monophosphate response element-binding protein (CREB), could play a role. We studied CREB in lung tissue from mice at different ages and in response to known age-related factors (e.g., cellular senescence and matrix modifications with advanced glycation end-products [AGEs]). Our study shows that protein but not mRNA levels of CREB are reduced in the lungs of old mice. CREB reduction was also observed in senescent human lung fibroblasts (WI-38, LuFi) and human lung epithelial cells (A549) cultured on AGE-modified collagen matrix. Reduction of CREB protein is partially based on pre- and posttranslational modifications as exhibited by an increase in the CREB-regulating microRNA 34b and CREB ubiquitination. Permanent down-regulation of CREB in lung cells impaired cell proliferation and viability and increased the number of cells with senescence-associated β-galactosidase activity. CREB down-regulation was accompanied by the reduced expression of 165 genes in WI-38 fibroblasts and A549 epithelial cells, of which 15 genes showed a reduced expression in lung tissues of old mice. The CREB-dependent reduction in RAB27A coding for the Ras-related protein Rab27A and IGFBP3 coding for the insulin-like growth factor-binding protein 3 has been confirmed for aged lung tissue, senescent fibroblasts, and lung epithelial cells on AGE-modified collagen. Our data demonstrate that the reduced protein expression of CREB might play a significant role in lung aging by modifying the transcription of RAB27A, IGFBP3, and other target genes.
authors.affiliation: 1 Department of Cardio-Thoracic Surgery, University Hospital Halle/Saale, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany.
authors.forename: Paulina
authors.initials: P
authors.lastname: Rolewska
authors.forename: Andreas
authors.initials: A
authors.lastname: Simm
authors.forename: Rolf-Edgar
authors.initials: RE
authors.lastname: Silber
authors.forename: Babett
authors.initials: B
authors.lastname: Bartling
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D000242:Cyclic AMP / Q000235:genetics* / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D046188:Protein Modification, Translational / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D054875:Ubiquitination / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D018972:Insulin-Like Growth Factor Binding Protein 3; D035683:MicroRNAs; D000242:Cyclic AMP; D001616:beta-Galactosidase; D020691:rab GTP-Binding Proteins