Reduced expression level of the cyclic adenosine monophosphate response element-binding protein contributes to lung...

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.