AP activation is known to upregulate

AP-1 activation is known to upregulate downstream target genes including MK-4827 Racemate D1, c-myc, Bcl-xl, MMP-9, EGFR, and specific miRNAs that are involved in progression and metastasis of tumors. Moreover, matrix metalloproteinase-2 has been shown as a downstream gene of AP-1, triggered by 15-HETE in the regulation of angiogenesis [19]. Furthermore, it has been reported that AP-1 signaling increased the expression of COX-2 and iNOS in mouse skin [24]. In the present study, we have confirmed that both hypoxia and 15-HETE induce cyclin D1 expression in an AP-1 dependent manner. In addition, we observed that the activation of AP-1 affects the expression of both 15-LOX1 and 15-LOX2, suggesting a reciprocal regulation between 15-LOX and AP-1. However, whether AP-1 directly binds to 15-LOX promoter or acts through other signaling pathways needs to be elucidated by further studies. Thus, these findings indicate that, in addition to the known downstream genes, 15-LOX is also a target of AP-1, and the reciprocal regulation between 15-LOX and AP-1 is involved in hypoxia-induced proliferation in PASMCs.
Introduction Olmsted syndrome (OS; Online Mendelian Inheritance in Man (OMIM) #614594) is a severe keratinization disorder characterized by the combination of palmoplantar and periorificial keratoderma and is often associated with hypotrichosis and intense itching [1]. OS is a very rare congenital disorder, and only 73 cases have been reported so far [1]. Most of the reported OS cases were sporadic; however, some familial cases with different hereditary patterns were also found. The hereditary patterns were either autosomal or X-linked and either dominant or recessive [1]. TRPV3 (transient receptor potential vanilloid subtype 3) on chromosome 17 and MBTPS2 (membrane-bound transcription factor protease, site 2) on chromosome X have been identified as the causative genes of OS [2], [3]. TRPV3 is a thermosensitive Ca2+ channel [4], [5], [6]. Most of the TRPV3 mutations (p.Gly573Ser, p.Gly573Cys, p.Gly573Ala, p.Gln580Pro, p.Leu673Phe, p.Trp692Gly, and p.Trp692Cys) found in OS patients were dominant [1], and expression of the mutant proteins caused increases in intracellular Ca2+ concentrations [2], [7]. Recessive mutations in TRPV3 have also been identified for OS [1], [8]. The reason why these diverse inheritance patterns exist for OS is currently unclear. The MBTPS2 mutations found in OS patients were recessive [3], [9]. MBTPS2 is a component of the regulated intramembrane proteolysis machinery that regulates cholesterol homeostasis and the unfolded protein response by cleaving membrane-spanning regulatory proteins [10]. TRPV3 belongs to the vanilloid family of transient receptor cation channels [11]. TRPV3 was shown to be highly expressed in skin, primarily in hair follicles and in keratinocytes that are present in the basal layer of the epidermis, and its expression has also been detected in brain, spinal cord, and dorsal root ganglion [5], [6]. TRPV3 is activated by temperature, with a threshold of 31–39°C [4], [5], [6], as well as by ligands such as 2-aminoethoxydiphenyl borate and farnesyl pyrophosphate, which is an intermediate metabolite of the mevalonate pathway [12], [13]. Furthermore, arachidonic acid and other unsaturated fatty acids were reported to potentiate TRPV3 activity [14], while the pro-resolving lipid mediator 17(R)-resolvin D1 was found to inhibit TRPV3 activity [15]. Thus, there appears to be a relationship between TRPV3 activity and lipids. WBN/Kob-Ht rats (hereafter called Ht rats) and DS-Nh mice were selected as spontaneous hairless rodent strains, and both strains had dominant Trpv3 mutations (p.Gly573Cys in Ht rats and p.Gly573Ser in DS-Nh mice), the same as two of the mutations found in OS patients [16]. These rodents developed dermatitis accompanied with hyperkeratosis and acanthosis under conventional conditions [17], [18]. The p.Gly573Ser transgenic mice also showed dermatitis with severe itching and defects in hair growth [19]. However, OS-like phenotypes were not observed in Trpv3 knockout mice; rather, they exhibited thin stratum corneum, wavy whiskers, and misaligned hair follicles [20], [21]. These results suggest that OS is caused by gain-of-function of TRPV3.