T-LAK Cell-originated Protein Kinase (TOPK) Phosphorylation of MKP1 Protein Prevents Solar Ultraviolet Light-induced Inflammation through Inhibition of the p38 Protein Signaling Pathway

Abstract

Solar UV radiation is a major environmental factor that causes DNA damage, inflammation, and even skin cancer. T-LAK cell-originated protein kinase (TOPK) is expressed widely in both normal and cancer cells and functions to inhibit apoptosis and promote carcinogenesis. However, its function in inflammation is not known. The p38 MAPK signaling pathway plays an important role in solar UV light-induced inflammation. In this study, we found that TOPK negatively regulated the activity of p38␣ by phosphorylating the p38␣-specific phosphatase MKP1 and enhancing the stability of MKP1. Notably, the absence of TOPK in mice resulted in a striking increase in skin inflammation. Therefore, we conclude that TOPK has a protective function in solar UV light-induced inflammation.UV light is a well established carcinogen of squamous-type tumors in mouse skin (1). UV light acts as both an initiator, presumably by causing DNA damage leading to gene mutations, and as a tumor promoter (2, 3). Because UV irradiation cannot penetrate farther than the skin in humans, this organ is the primary target for UV light-induced damage and carcinogenesis. Solar UV light can be very harmful to human health, causing DNA damage, inflammation, erythema, sunburn, immunosuppression, photoaging, gene mutations, and skin cancer (4). The inflammation produced by exposure to UV light has been well documented clinically and histologically (5). The MAPKs, especially p38, have been reported to be involved in UV light-induced inflammation and related signal transduction (4).The p38 MAPK pathway is a key regulator of proinflammatory cytokine biosynthesis, including TNF-␣, IL-1␤, and cyclooxygenase-2, at the transcriptional and translational levels (6). In addition, p38 also acts downstream of cytokines, such as TNF-␣, mediating some of their effects. Thus, p38 has been the subject of extensive efforts in both basic research and drug discovery (7). The p38 protein can be phosphorylated by MKK3 and MKK6 within a few minutes after exposure to diverse stimuli (8). The MAPK phosphatase MKP1, an archetypal member of the MKP family, plays a pivotal role in the deactivation of p38 through a dephosphorylation reaction. Studies using MKP1 knock-out mice have defined the critical importance of MKP1 in the regulation of proinflammatory cytokine synthesis in vivo during the host response to Toll-like receptor ligands (9). Our kinase array assay indicated that the p38 protein is activated strongly by solar UV radiation 3 and therefore might play a pivotal role in solar UV light-induced inflammation.T-LAK cell-originated protein kinase (TOPK), 4 a newly identified member of the MEK3/6-related MAPKK family, is expressed in a wide range of proliferating cells and tissues, including cancer cells and testis. TOPK (Thr-9) is phosphorylated by the Cdk1-cyclin B complex and associates with mitotic spindles during mitosis (10). TOPK phosphorylation of histone H2AX prevents arsenite-induced apoptosis in RPMI7951 melanoma cells (11). A positive feedback loop occurs between TOPK and ER...

Phosphorylation of IκBα at Serine 32 by T-lymphokine-activated Killer Cell-originated Protein Kinase Is Essential for Chemoresistance against Doxorubicin in Cervical Cancer Cells

“…It has been suggested that some stimuli including TPA or UVB positively regulate TOPK activity (12,17,19). However, information about signaling pathways or stimuli triggering TOPK activation is still lacking.…”

“…We demonstrate here that TOPK functions as a novel target molecule of doxorubicin, implying a critical role for TOPK in doxorubicin-induced cervical cancer cell death. Some molecules, such as p38 MAPK, JNK, phosphatase MKP1, and peroxiredoxin 1, have been proposed to act as downstream substrates for TOPK (12,(17)(18)(19). However, evidence for downstream targets of TOPK still remains elusive.…”

“…It has been proposed that TOPK, MAPKK-like protein kinase, acts as an upstream kinase for p38 MAPK, phosphatase MKP1, and peroxiredoxin 1 (12,17,18). In addition, TOPK phosphorylates JNK1 in UVBmediated signaling or Ras-induced cell transformation and positively regulates ERK2 during tumorigenesis (19,20).…”

PBK/TOPK expression correlates with mutant p53 and affects patients' prognosis and cell proliferation and viability in lung adenocarcinoma

“…High TOPK expression can promote cell proliferation [11][12][13] and prevent apoptosis [14,15] and is associated with a poor prognosis [16][17][18][19]. Moreover, TOPK expression may play an important role in the progress of cytokinesis and inflammation [20][21][22]. However, the detailed mechanism of TOPK signaling in lung adenocarcinoma remains unclarified.…”

Chronic inflammatory cells and damaged limbal cells in pterygium

“…22 This would seem to suggest that a hereditary predisposition may be the reason that inflammation was severe in some pterygia. Failure to detect MMP expression in fibroblasts or stroma contradicts a previous report, 7 perhaps due to persistent exposure to sunlight without wearing spectacles which may reduce UV radiation reaching the eyes.…”