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)

Potential targets for chemoprevention of nonmelanoma skin cancer include UV-induced nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1) activation in keratinocytes. Inhibition of both these ultraviolet light B (UVB)-induced transcription factors has been shown with the dominant-negative c-jun mutant, TAM67; however, its mechanism of action has not yet been determined. Here we demonstrated that transient transfection of a mouse keratinocyte cell line (308) with a dominant-negative phosphorylation mutant of c-Jun before exposure to 250 J/m(2) UVB inhibits transactivation mediated by both AP-1 and NF-kappaB transcription factors to levels below those of UVB exposed controls. Through the utilization of immunoprecipitation techniques, protein-protein interactions between NF-kappaB family members IkappaBalpha, IkappaBbeta, p50, and p65 (Rel-A) were identified with an Xpress tagged dominant-negative c-Jun (TAM67) protein. Expression of the leucine zipper domain of the TAM67 protein inhibited UVB-induced NF-kappaB transactivation but not AP-1 transactivation. Expression of the bZIP domain of the TAM67 protein was able to inhibit transactivation mediated by both transcription factors. These data demonstrate that TAM67 is able to inhibit two significant UVB-induced molecular targets AP-1 and NF-kappaB, and that the inhibition of these two transcription factor families is potentially due to protein-protein interactions between different regions of the dominant-negative c-Jun protein.
 ...
PMID:Differential inhibition of UVB-induced AP-1 and NF-kappaB transactivation by components of the jun bZIP domain. 1579 49

The epidermal growth factor receptor (EGFR) is activated in skin cells following UV irradiation, the primary cause of nonmelanoma skin cancer. The EGFR inhibitor AG1478 prevented the UV-induced activation of EGFR and of downstream signaling pathways through c-Jun NH2-terminal kinases, extracellular signal-regulated kinases, p38 kinase, and phosphatidylinositol 3-kinase in the skin. The extent to which the UV-induced activation of EGFR influences skin tumorigenesis was determined in genetically initiated v-ras(Ha) transgenic Tg.AC mice, which have enhanced susceptibility to skin carcinogenesis. Topical treatment or i.p. injection of AG1478 before UV exposure blocked the UV-induced activation of EGFR in the skin and decreased skin tumorigenesis in Tg.AC mice. AG1478 treatment before each of several UV exposures decreased the number of papillomas arising and the growth of these tumors by approximately 50% and 80%, respectively. Inhibition of EGFR suppressed proliferation, increased apoptotic cell death, and delayed the onset of epidermal hyperplasia following UV irradiation. Genetic ablation of Egfr similarly delayed epidermal hyperplasia in response to UV exposure. Thus, the UV-induced activation of EGFR promotes skin tumorigenesis by suppressing cell death, augmenting cell proliferation, and accelerating epidermal hyperplasia in response to UV. These results suggest that EGFR may be an appropriate target for the chemoprevention of UV-induced skin cancer.
 ...
PMID:Chemoprevention of UV light-induced skin tumorigenesis by inhibition of the epidermal growth factor receptor. 1586 97

UVB radiation is the major etiologic factor in the development of nonmelanoma skin cancer. In addition to tumor-initiating effect, UVB also causes tumor promotion via mitogenic and survival signaling. Studies have shown strong preventive effects of silibinin against both UVB-induced and chemically induced tumor promotion in mouse skin models; however, mechanisms are not understood completely. Here, we used tumor promoter-sensitive JB6 mouse epithelial cell model and studied the effect of silibinin on two different mitogens [UVB and epidermal growth factor (EGF)] that induce mitogenic and cell survival signaling pathways. UVB (50-800 mJ/cm(2)) dose-dependently induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun-NH(2)-kinase 1/2 (JNK1/2), and p38 kinase (p38K) as well as Akt, with an optimum response at 400 mJ/cm(2) UVB dose. UVB caused a biphasic phosphorylation of ERK1/2 in a time kinetics study. Silibinin treatment before or immediately after UVB exposure, or both, resulted in a strong decrease in UVB-caused phosphorylation of ERK1/2 and Akt in both dose- and time-dependent manner, without any substantial response on JNK1/2 and p38K. Silibinin also suppressed UVB-induced activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) activation, which are activated by ERK1/2 and Akt. Silibinin treatment under similar conditions also strongly inhibited EGF-induced ERK1/2, JNK1/2, and p38K as well as Akt phosphorylation, and also suppressed EGF-induced AP-1 and NF-kappaB activation. Because AP-1 and NF-kappaB are important nuclear transcription factors for tumor promotion, these results suggest that silibinin possibly prevents skin tumor promotion by inhibiting UVB- and EGF-induced mitogenic and cell survival signaling involving both AP-1 and NF-kappaB.
 ...
PMID:Silibinin inhibits UVB- and epidermal growth factor-induced mitogenic and cell survival signaling involving activator protein-1 and nuclear factor-kappaB in mouse epidermal JB6 cells. 1673 46

Sperm-associated antigen 9 (SPAG9) is a scaffold protein for c-Jun-NH2-kinases, which play an important role in cell survival, proliferation, apoptosis, and tumor development. SPAG9 was claimed to be involved in the pathogenesis of carcinoma in different organs. The aim of this work was to investigate its role in the pathogenesis of nonmelanoma skin cancer (NMSC) through its immunohistochemical (IHC) localization in skin biopsies of these tumors. This retrospective and prospective study included 67 cutaneous specimens; 42 of NMSC [20 cases with basal cell carcinoma (BCC) and 22 cases with squamous cell carcinoma (SCC)] and 25 normal sun-exposed skin biopsies from age and gender-matched healthy subjects as a control group. SPAG9 expression was evaluated using standard IHC techniques. SPAG9 was expressed in 90% of BCC cases and in 81.8% of SCC cases. Positive expression in inflammatory cells was detected in 100% and 63.6% of BCC and SCC cases, respectively. Positive stromal expression was detected in 20% of BCC cases and was absent in all SCC cases. A significant negative correlation (r = -0.55, P = 0.008) was noted between SPAG9 H score and SCC histological grade and a significant association between SPAG9 H score and tumor grade was also detected where higher values were present in grade I tumors (P = 0.001). SPAG9 was upregulated in NMSC when compared with normal skin. In conclusion, SPAG9 is expressed in NMSC cases. It should be evaluated in large-scale studies to determine if it plays an active pathogenic role or its expression is an epiphenomenon not related to NMSC pathogenesis. Large-scale studies are warranted to determine its potential utility in guiding treatment decisions and following disease progression in theses cases. Its expression in normal skin needs further investigation.
 ...
PMID:Immunohistochemical expression of sperm-associated antigen 9 in nonmelanoma skin cancer. 2503 8