AP-1 Signaling Activates MMP in Chronological and Photo Skin Aging

The activator protein 1 (AP-1) is a heterodimeric transcription factor belonging to the c-Fos, c-Jun, ATF and JDP families. It regulates and activates genes in response to a variety of stimuli including stress, pathogen infections, cytokines, growth factors. AP-1 thereby regulates a number of cellular processes including differentiation, proliferation, and apoptosis. AP-1 binds to the TPA DNA response element via its DNA binding domain – leucine zipper DNA binding domain. AP-1 signaling pathway is also involved in the chronological and photo skin aging. The most common stimuli is by the production of reactive oxygen species (ROS). As is known, oxidative stress is one of the main mechanisms for both chronological skin aging and photo skin aging. Increased oxidative stress and accumulation of ROS are observed in intrinsic and extrinsic aging process. ROS not only damage biomacromolecules and cellular components, but also activate the signal transduction pathways which lead to the activation of genes such as the matrix degrading enzymes – matrix metalloproteinase (MMP). Increased level of MMPs are observed in both intrinsic and extrinsic aging process, resulting in the degradation of collagen and elastic fiber networks of the dermal connective tissue.

Dysregulation of intracellular and extracellular homeostasis in the skin by the ROS and the genes activated by ROS induced signal transduction pathway. ROS are necessary participants in multiple MAP kinase pathways. MAP kinase activation results in induction of transcription factor AP-1 that is a major effector of the MAP kinase pathways. AP-1 is increased in aged human skin in vivo and aged skin fibroblasts in vitro. AP-1 transcription factor is composed of two subunits: c-fos and c-jun. In human skin, AP-1 activity is limited by c-jun level while c-fos is constant. c-Jun level is increased in aged skin while c-fos remain same. Among genes regulated by AP-1 are several matrix-metalloproteinase (MMP) and type I procollagen. AP-1 activate MMPs directly and decrease type I procollagen indirectly through activating Smad7. Increased production of MMP-1, MMP-2 (gelatinase A), MMP-3, and MMP-9 occurs in chronologically aged skin and photo aged skin. With the exception of MMP-2, these MMPs are regulated by AP-1. Transcription of several MMP (matrix-metalloproteinase) family members is strongly activated by AP-1. These include MMP-1 (interstitial collagenase or collagenase 1) which initiates degradation of types I and III fibrillar collagens, MMP-9 (gelatinase B), which further degrades collagen fragments generated by collagenases, and MMP-3 (stromelysin 1), which degrades type IV collagen of the basement membrane and activates proMMP-1.

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