ABSTRACT
PHRF1 (PHD and RING finger domain-containing protein 1) suppresses acute promyelocytic leukemia (APL) by promoting TGIF (TG-interacting factor) ubiquitination, while the PML-RARα protein interferes with PHRF1-mediated TGIF breakdown to facilitate APL. Beyond its role in APL tumorigenesis, PHRF1 contributes to non-homologous end-joining by linking H3K36 methylation and Nbs1 upon DNA damage insults. However, little is known regarding its function in tumor invasion. Here we highlight the unreported details of PHRF1 in the invasion of lung cancer cells by modulating the transcriptional level of ZEB1, a prominent regulator involved in epithelial-mesenchymal transition. PHRF1 associated with the phosphorylated C-terminal repeat domain of Rpb1, the large subunit of RNA polymerase II, through its C-terminal Set2 Rpb1 Interacting (SRI) domain. Chromatin immunoprecipitation revealed that PHRF1 bound to the proximal region adjacent to the transcription start site of ZEB1. SRI-deleted PHRF1 neither associated with Rpb1 nor increased ZEB1's expression. Collectively, PHRF1 might take the stage at migration and invasion by modulating the expression of ZEB1.
Subject(s)
Cell Movement , Lung Neoplasms/pathology , Membrane Proteins/metabolism , Zinc Finger E-box-Binding Homeobox 1/metabolism , Animals , Apoptosis , Biomarkers, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Membrane Proteins/genetics , Mice , Neoplasm Invasiveness , Prognosis , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , Zinc Finger E-box-Binding Homeobox 1/geneticsABSTRACT
Vilse/Arhgap39 is a Rho GTPase activating protein (RhoGAP) and utilizes its WW domain to regulate Rac/Cdc42-dependent morphogenesis in Drosophila and murine hippocampal neurons. However, the function of Vilse in mammalian dendrite architecture and synaptic plasticity remained unclear. In the present study, we aimed to explore the possible role of Vilse in dendritic structure and synaptic function in the brain. Homozygous knockout of Vilse resulted in premature embryonic lethality in mice. Changes in dendritic complexity and spine density were noticed in hippocampal neurons of Camk2a-Cre mediated forebrain-specific Vilse knockout (VilseΔ/Δ) mice. VilseΔ/Δ mice displayed impaired spatial memory in water maze and Y-maze tests. Electrical stimulation in hippocampal CA1 region revealed that the synaptic transmission and plasticity were defected in VilseΔ/Δ mice. Collectively, our results demonstrate that Vilse is essential for embryonic development and required for spatial memory.