NF-κB accumulation associated with COL1A1 transactivators defects during chronological aging represses type I collagen expression through a -112/-61-bp region of the COL1A1 promoter in human skin fibroblasts.
The aging process, especially of the skin, is governed by changes in the epidermal, dermo-epidermal, and dermal compartments. Type I collagen, which is the major component of dermis extracellular matrix (ECM), constitutes a prime target for intrinsic and extrinsic aging-related alterations. In addition, under the aging process, pro-inflammatory signals are involved and collagens are fragmented owing to enhanced matrix metalloproteinase activities, and fibroblasts are no longer able to properly synthesize collagen fibrils. Here, we demonstrated that low levels of type I collagen detected in aged skin fibroblasts are attributable to an inhibition of COL1A1 transcription. Indeed, on one hand, we observed decreased binding activities of specific proteins 1 and 3, CCAAT-binding factor, and human collagen-Krüppel box, which are well-known COL1A1 transactivators acting through the -112/-61-bp promoter sequence. On the other hand, the aging process was accompanied by elevated amounts and binding activities of NF-κB (p65 and p50 subunits), together with an increased number of senescent cells. The forced expression of NF-κB performed in young fibroblasts was able to establish an old-like phenotype by repressing COL1A1 expression through the short -112/-61-bp COL1A1 promoter and by elevating the senescent cell distribution. The concomitant decrease of transactivator functions and increase of transinhibitor activity is responsible for ECM dysfunction, leading to aging/senescence in dermal fibroblasts.
Laboratoire Matrice Extracellulaire et Pathologie, IFR ICORE 146, Université de Caen/Basse-Normandie, UFR de Médecine, Caen, France.
Nicolas
N
Bigot
Laboratoire Matrice Extracellulaire et Pathologie, IFR ICORE 146, Université de Caen/Basse-Normandie, UFR de Médecine, Caen, France.
Gallic
G
Beauchef
Laboratoire Matrice Extracellulaire et Pathologie, IFR ICORE 146, Université de Caen/Basse-Normandie, UFR de Médecine, Caen, France.
Magalie
M
Hervieu
Department of Pharmacology, Johnson&Johnson Santé Beauté France, Val de Reuil, France.
Thierry
T
Oddos
Laboratoire Matrice Extracellulaire et Pathologie, IFR ICORE 146, Université de Caen/Basse-Normandie, UFR de Médecine, Caen, France.
Magali
M
Demoor
Laboratoire Matrice Extracellulaire et Pathologie, IFR ICORE 146, Université de Caen/Basse-Normandie, UFR de Médecine, Caen, France.
Karim
K
Boumediene
Laboratoire Matrice Extracellulaire et Pathologie, IFR ICORE 146, Université de Caen/Basse-Normandie, UFR de Médecine, Caen, France. Electronic address: philippe.galera@unicaen.fr.
Philippe
P
Galéra
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism*; D023081:CCAAT-Binding Factor / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D024042:Collagen Type I / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000502:physiology*; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D055815:Young Adult
D023081:CCAAT-Binding Factor; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016328:NF-kappa B; D016329:Sp1 Transcription Factor; D015534:Trans-Activators; D051705:Sp3 Transcription Factor