Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ultraviolet radiation from the sun damages human skin, resulting in an old and wrinkled appearance. A substantial amount of circumstantial evidence indicates that photoaging results in part from alterations in the composition, organization, and structure of the collagenous extracellular matrix in the dermis. This paper reviews the authors' investigations into the molecular mechanisms by which ultraviolet irradiation damages the dermal extracellular matrix and provides evidence for prevention of this damage by all-trans retinoic acid in human skin in vivo. Based on experimental evidence a working model is proposed whereby ultraviolet irradiation activates growth factor and cytokine receptors on keratinocytes and dermal cells, resulting in downstream signal transduction through activation of MAP kinase pathways. These signaling pathways converge in the nucleus of cells to induce c-Jun, which heterodimerizes with constitutively expressed c-Fos to form activated complexes of the transcription factor AP-1. In the dermis and epidermis, AP-1 induces expression of matrix metalloproteinases collagenase, 92 kDa gelatinase, and stromelysin, which degrade collagen and other proteins that comprise the dermal extracellular matrix. It is hypothesized that dermal breakdown is followed by repair that, like all wound repair, is imperfect. Imperfect repair yields a deficit in the structural integrity of the dermis, a solar scar. Dermal degradation followed by imperfect repair is repeated with each intermittent exposure to ultraviolet irradiation, leading to accumulation of solar scarring, and ultimately visible photoaging. All-trans retinoic acid acts to inhibit induction of c-Jun protein by ultraviolet irradiation, thereby preventing increased matrix metalloproteinases and ensuing dermal damage.
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PMID:Molecular mechanisms of photoaging and its prevention by retinoic acid: ultraviolet irradiation induces MAP kinase signal transduction cascades that induce Ap-1-regulated matrix metalloproteinases that degrade human skin in vivo. 973 61

Biopsies from patients with cutaneous T-cell lymphoma (CTCL) exhibit stage-dependent increase in angiogenesis. However, the molecular mechanisms responsible for the increased angiogenesis are unknown. Here we show that malignant CTCL T cells spontaneously produce the potent angiogenic protein, vascular endothelial growth factor (VEGF). Dermal infiltrates of CTCL lesions show frequent and intense staining with anti-VEGF antibody, indicating a steady, high production of VEGF in vivo. Moreover, the VEGF production is associated with constitutive activity of Janus kinase 3 (Jak3) and the c-Jun N-terminal kinases (JNKs). Sp600125, an inhibitor of JNK activity and activator protein-1 (AP-1) binding to the VEGF promoter, downregulates the VEGF production without affecting Jak3 activity. Similarly, inhibitors of Jak3 inhibit the VEGF production without affecting JNK activity. Downregulation of Stat3 with small interfering RNA has no effect, whereas curcumin, an inhibitor of both Jak3 and the JNKs, almost completely blocks the VEGF production. In conclusion, we provide evidence of VEGF production in CTCL, which is promoted by aberrant activation of Jak3 and the JNKs. Inhibition of VEGF-inducing pathways or neutralization of VEGF itself could represent novel therapeutic modalities in CTCL.
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PMID:Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma. 1693 49