@article {218, title = {Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells.}, journal = {Oncotarget}, volume = {6}, year = {2015}, month = {2015 Feb 28}, pages = {4357-68}, abstract = {

Alterations of the EGFR/ERK and Hippo/YAP pathway have been found in non-small cell lung cancer (NSCLC). Herein, we show that ERK1 and ERK2 have an effect on the Hippo/YAP pathway in human NSCLC cells. Firstly, inhibition of ERK1/2 by siRNA or small-molecular inhibitors decreased the YAP protein level, the reporter activity of the Hippo pathway, and the mRNA levels of the Hippo downstream genes, CTGF, Gli2, and BIRC5. Secondly, degradation of YAP protein was accelerated after ERK1/2 depletion in NSCLC cell lines, in which YAP mRNA level was not decreased. Thirdly, forced over-expression of the ERK2 gene rescued the YAP protein level and Hippo reporter activity after siRNA knockdown targeting 3{\textquoteright}UTR of the ERK2 gene in NSCLC cells. Fourthly, depletion of ERK1/2 reduced the migration and invasion of NSCLC cells. Combined depletion of ERK1/2 had a greater effect on cell migration than depletion of either one separately. Finally, the MEK1/2 inhibitor Trametinib decreased YAP protein level and transcriptional activity of the Hippo pathway in NSCLC cell lines. Our results suggest that ERK1/2 inhibition participates in reducing YAP protein level, which in turn down-regulates expression of the downstream genes of the Hippo pathway to suppress migration and invasion of NSCLC cells.

}, keywords = {Adaptor Proteins, Signal Transducing, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Movement, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Lung Neoplasms, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Neoplasm Invasiveness, Phosphoproteins, Protein-Serine-Threonine Kinases, Real-Time Polymerase Chain Reaction, RNA, Small Interfering, Signal Transduction, Transfection}, issn = {1949-2553}, doi = {10.18632/oncotarget.2974}, author = {You, Bin and Yang, Yi-Lin and Xu, Zhidong and Dai, Yuyuan and Liu, Shu and Jiang-Hua Mao and Tetsu, Osamu and Li, Hui and Jablons, David M and You, Liang} } @article {221, title = {PR-Set7 is Degraded in a Conditional Cul4A Transgenic Mouse Model of Lung Cancer.}, journal = {Zhongguo Fei Ai Za Zhi}, volume = {18}, year = {2015}, month = {2015 Jun}, pages = {345-50}, abstract = {

BACKGROUND: Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. PR-Set7 (also known as Set8) is a cell cycle regulated enzyme that catalyses monomethylation of histone 4 at Lys20 (H4K20me1) to promote chromosome condensation and prevent DNA damage. Recent studies show that CRL4CDT2-mediated ubiquitylation of PR-Set7 leads to its degradation during S phase and after DNA damage. This might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity after DNA damage.

METHODS: We developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. We have therefore used a mouse model to demonstrate for the first time that Cul4A is oncogenic in vivo. With this model, staining of PR-Set7 in the preneoplastic and tumor lesions in AdenoCre-induced mouse lungs was performed. Meanwhile we identified higher protein level changes of γ-tubulin and pericentrin by IHC.

RESULTS: The level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identified higher levels of the proteins pericentrin and γ-tubulin in Cul4A mouse lungs induced by AdenoCre.

CONCLUSIONS: PR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model.

}, keywords = {Animals, Cell Cycle, Cullin Proteins, Disease Models, Animal, Down-Regulation, Histone-Lysine N-Methyltransferase, Histones, Humans, Lung, Lung Neoplasms, Mice, Mice, Transgenic, Proteolysis, Tubulin}, issn = {1999-6187}, doi = {10.3779/j.issn.1009-3419.2015.06.15}, author = {Wang, Yang and Xu, Zhidong and Jiang-Hua Mao and Hsieh, David and Au, Alfred and Jablons, David M and Li, Hui and You, Liang} }