RGD Reference Report - Impaired activation of AP-1 and altered expression of constituent proteins in rat adrenal during ageing. - Rat Genome Database

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Impaired activation of AP-1 and altered expression of constituent proteins in rat adrenal during ageing.

Authors: Medicherla, R  Leers-Sucheta, S  Luo, Y  Azhar, S 
Citation: Medicherla R, etal., Mech Ageing Dev. 2001 Aug;122(11):1169-86.
RGD ID: 2293789
Pubmed: PMID:11389931   (View Abstract at PubMed)

Oxidative stress appears to be one of the primary factors contributing to an age related decline in steroidogenic response in rat adrenocortical and testicular Leydig cells. In this report we concentrate on age-related changes in the DNA binding activity of the transcription factor AP-1 which is particularly responsive to changes in cellular oxidative conditions: adrenal nuclear extracts from young mature (5 months) and old (24 months) rats treated with, and without, lipopolysaccharide (LPS) were studied. AP-1 binding activity, as measured by electrophoretic mobility shift assays (EMSA), was diminished approximately 70% with age in unstimulated adrenals. Following LPS treatment, AP-1 binding activity increased significantly in the adrenals of both young and old animals; however, the level of AP-1 binding achieved in LPS-stimulated old rats was less than that observed for LPS-stimulated young rats. There was no corresponding change in the binding activity of housekeeping transcription factors SP-1 and OCT-1. To further understand these observations, compositional changes in the members of the AP-1 DNA-binding complex were examined by a super-shift assay and Western blot analysis. In adrenals from old rats, a significant decrease in the amount of Fra2 was noted under basal conditions, whereas, substantial decreases in c-Fos, Jun D and c-Jun were observed in response to LPS treatment. In contrast, basal levels of JunB, an inhibitor of the trans-activating function of c-Jun and repressor of AP-1-dependent transcription, were significantly elevated in adrenals from old rats compared to young rats. Together, these findings suggest that ageing-induced oxidative stress may contribute to impaired functional expression of AP-1 by differentially regulating the steady state levels of AP-1 components. The observed decrease in AP-1 binding activity in ageing adrenals is most likely due to decreased expression of the AP-1 activating components (c-Fos, c-Jun, JunD, etc.) and increased expression of JunB, resulting in a switch from transcriptionally active AP-1 complexes observed in young rats to less efficient JunB containing complexes in old rats.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to lipopolysaccharide  IEP 2293789; 2293789; 2293789 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Fos  (Fos proto-oncogene, AP-1 transcription factor subunit)
Jun  (Jun proto-oncogene, AP-1 transcription factor subunit)
Jund  (JunD proto-oncogene, AP-1 transcription factor subunit)

Objects referenced in this article
Gene Fosl2 FOS like 2, AP-1 transcription factor subunit Rattus norvegicus

Additional Information