Abstract
Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) plays a great role in tumor cell growth, but its function and mechanism in cell invasive behavior are totally unknown. Here we report that NEDD4-1 regulates migration and invasion of malignant glioma cells via triggering ubiquitination of cyclic nucleotide Ras guanine nucleotide exchange factor (CNrasGEF) using cultured glioma cells. NEDD4-1 overexpression promoted cell migration and invasion, while its downregulation specifically inhibited them. However, NEDD4-1 did not affect the proliferation and apoptosis of glioma cells. NEDD4-1 physically interacted with CNrasGEF and promoted its poly-ubiquitination and degradation. Contrary to the effect of NEDD4-1, CNrasGEF downregulation promoted cell migration and invasion, while its overexpression inhibited them. Importantly, downregulation of CNrasGEF facilitated the effect of NEDD4-1-induced cell migration and invasion. Interestingly, aberrant up-regulated NEDD4-1 showed reverse correlation with CNrasGEF protein level but not with its mRNA level in glioma tissues. Combined with the in vitro results, the result of glioma tissues indicated post-translationally modification effect of NEDD4-1 on CNrasGEF. Our study suggests that NEDD4-1 regulates cell migration and invasion through ubiquitination of CNrasGEF in vitro.
Highlights
Malignant glioma is the most common and lethal tumor in the central nervous system and is histologically graded as I-IV by World Health Organization (WHO) based on four main features-nuclear atypia, mitosis, microvascular enrichment, and necrosis[1,2,3]
We found that the GFP transfection efficiency was as high as 65% and the number of migratory GFP positive cells in Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) overexpressing group increased by 63% (*P
The above results indicate that the effect of NEDD4-1 on glioma cell migration was really induced by NEDD4-1 manipulation and was not caused by nontransfection cells
Summary
Malignant glioma is the most common and lethal tumor in the central nervous system and is histologically graded as I-IV by World Health Organization (WHO) based on four main features-nuclear atypia, mitosis, microvascular enrichment, and necrosis[1,2,3]. Seeking molecular mechanisms of glioma invasiveness is expected to develop effective therapeutic targets for this incurable cancer [4]. NEDD4-1 regulates many physiological functions, such as cellular proliferation and organism growth, water balance, T cell function [26], the development of neuromuscular junction [27], development of central nervous system and axon guidance [16,28,29], and brain diseases [30,31]. NEDD4-1 positively regulates growth and proliferation of cells especially during embryonic development and NEDD4-1 knockout induces growth retardation and associated perinatal lethality [32]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call