Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar Node, Navi Mumbai, Maharashtra, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, India.
Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, India.
Exp Cell Res. 2018 Aug 15;369(2):251-265. doi: 10.1016/j.yexcr.2018.05.026. Epub 2018 May 24.
An increase in tumour formation and metastasis are observed upon plakophilin3 (PKP3) loss. To identify pathways downstream of PKP3 loss that are required for increased tumour formation, a gene expression analysis was performed, which demonstrated that the expression of lipocalin2 (LCN2) was elevated upon PKP3 loss and this is consistent with expression data from human tumour samples suggesting that PKP3 loss correlates with an increase in LCN2 expression. PKP3 loss leads to an increase in invasion, tumour formation and metastasis and these phenotypes were dependent on the increase in LCN2 expression. The increased LCN2 expression was due to an increase in the activation of p38 MAPK in the HCT116 derived PKP3 knockdown clones as LCN2 expression decreased upon inhibition of p38 MAPK. The phosphorylated active form of p38 MAPK is translocated to the nucleus upon PKP3 loss and is dependent on complex formation between p38 MAPK and PKP3. WT PKP3 inhibits LCN2 reporter activity in PKP3 knockdown cells but a PKP3 mutant that fails to form a complex with p38 MAPK cannot suppress LCN2 promoter activity. Further, LCN2 expression is decreased upon loss of p38β, but not p38α, in the PKP3 knockdown cells. These results suggest that PKP3 loss leads to an increase in the nuclear translocation of p38 MAPK and p38β MAPK is required for the increase in LCN2 expression.
在 plakophilin3（PKP3）缺失的情况下，观察到肿瘤形成和转移增加。为了确定 PKP3 缺失下游的通路，这些通路是增加肿瘤形成所必需的，进行了基因表达分析，结果表明，lipocalin2（LCN2）的表达在 PKP3 缺失时升高，这与人类肿瘤样本的表达数据一致，表明 PKP3 缺失与 LCN2 表达增加相关。PKP3 缺失导致侵袭、肿瘤形成和转移增加，这些表型依赖于 LCN2 表达的增加。LCN2 表达的增加是由于 HCT116 衍生的 PKP3 敲低克隆中 p38 MAPK 的激活增加所致，因为 LCN2 表达在 p38 MAPK 抑制后降低。磷酸化的活性形式的 p38 MAPK 在 PKP3 缺失后易位到核内，并且依赖于 p38 MAPK 和 PKP3 之间的复合物形成。WT PKP3 抑制 PKP3 敲低细胞中的 LCN2 报告基因活性，但不能与 p38 MAPK 形成复合物的 PKP3 突变体不能抑制 LCN2 启动子活性。此外，在 PKP3 敲低细胞中，p38β 缺失而不是 p38α 缺失会导致 LCN2 表达降低。这些结果表明，PKP3 缺失导致 p38 MAPK 的核易位增加，p38β MAPK 是 LCN2 表达增加所必需的。
