SMEK1 promotes clear cell Renal Cell Carcinoma progression via EGFR tyrosine-kinase dependent pathway.

Studying the mechanisms underlying clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, may address an unmet need in ccRCC-targeted drug research. Growing evidences indicate that protein phosphatase 4 (PP4) plays an important role in cancer biology. Here, we characterized the upregulation of PP4 core component SMEK1 in ccRCC using tissue microarrays and revealed that its high expression is closely associated with reduced patient survival. We then conducted cell function experiments and animal experiments to prove the tumor-promoting effect of SMEK1. Next, RNA-seq was performed to explore its underlying mechanism, and the results revealed that SMEK1-regulated genes were extensively involved in cell motility, and the canonical tyrosine kinase receptor EGFR was one of its targets. Moreover, we verified the regulatory effect of SMEK1 on EGFR and its downstream MAPK and AKT pathway through molecular experiments, in which erlotinib, a tyrosine kinase inhibitor, can partially block this regulation, demonstrating that SMEK1 mediates its effects dependent on the tyrosine kinase activity of EGFR. Mechanistically, SMEK1 bond to PRMT5 and facilitated PRMT5-mediated histone methylation to promote the transcription of EGFR. Furthermore, we studied the upstream regulators of SMEK1 and demonstrated that the transcription factor E2F1 could directly bind to the SMEK1 promoter by chromatin immunoprecipitation. Functionally, E2F1 could also induce ccRCC progression by manipulating the expression of SMEK1. Collectively, our findings demonstrate the overexpression of SMEK1 in ccRCC, and reveal a novel E2F1/SMEK1/PRMT5/EGFR-tyrosine-kinase-dependent pathway for ccRCC progression.

Cooperative group formation control for multiple quadrotors system with finite- and fixed-time convergence.

A multitude of quadrotors cooperatively executing complicated tasks in predefined geometric configurations has attracted arising attention. Accurate and effective formation control laws are essential for completing missions. Finite- and fixed-time group formation control problems for multiple quadrotors are researched in this paper. The quadrotors are first divided into M distinct and non-overlapping subgroups. In each subgroup, quadrotors are driven to form the predefined configuration, with the whole achieving M-group formation meanwhile. Two distributed algorithms for multiple quadrotors system are then designed to realize finite- and fixed-time group formation. Detailed and theoretical analysis of finite- and fixed-time group formation formability is conducted. Sufficient conditions are provided by utilizing the Lyapunov stability and bi-limit homogeneity theory. Two simulations are carried out to verify the effectiveness of proposed algorithms.