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.