ABSTRACT
Protein post-translational modification is a precondition guaranteeing normal exertion of protein functions. Ubiquitination is an important post-translational modification that maintains normal protein levels and activity. Numerous researches show that the E3 ubiquitin ligase speckle-type POZ protein (SPOP) displays mutations in many tumors and genetic diseases. Mainly concentrated in the MATH structural domain that recognizes substrates, these mutations influence the binding between SPOP and substrates, and further influence their protein levels, positioning and activities, thus disturbing the normal physiological functions. Wild-type SPOP binds the substrates, most of which enter the proteasome pathway for decomposition after being ubiquitinated by SPOP, but some substrates are also influenced functionally. Herein we review the ubiquitination types and functions of SPOP substrates, including the ubiquitin-proteasome system (UPS), structure, functions and molecular pathways of SPOP, and non-degradative ubiquitinated modification of SPOP. The emphasis will be laid on the molecular mechanisms of the signaling pathways mediated by the three non-degradative substrates of SPOP, that is, myeloid differentiation primary response gene 88 (MyD88)-mediated NF-κB pathway, X-chromosome silence signal pathway of histone macroH2A1 (macroH2A. 1 histone, macroH2A1), and inverted formin 2 (INF2)mediated chondriokinesis pathway, in inhibiting tumorigenesis and development. We expect to provide a new perspective for precise targeted therapies of tumors.
ABSTRACT
Objective To explore the activity of brain default mode network (DMN) in patients with mild Alzheimer's disease (AD) by resting state functional magnetic resonance imaging (fMRI) and investigate its possible neural mechanism. Methods Twenty-four patients with mild AD,admitted to our hospital from January 2009 to June 2010,and 25 normal controls (NCs) were chosen in this study.All subjects were examined by Mini Mental State Examination (MMSE), Mattis Dementia Rating Scale (DRS) and fMRI.Resting-state whole brain data were analyzed by amplitude of low frequency fluctuation (ALFF) with two-sample t test and the brain regions in mild AD patients having significantly different ALFF comparing to NCs were observed. Results As compared with that in NCs,the memory function in mild AD patients was seriously impaired (P＜0.05).As compared with NCs,mild AD patients showed significantly decreased ALFF in the posterior cingulate cortex,ventral medial prefrontal cortex and dorsal medial prefrontal cortex, which were closely relevant to the memory (P＜0.05). Conclusion AD patients show significantly decreased active intensity of some DMN nodes that relate to memory in resting state; DMN abnormalities play an important role in early memory impairment of AD patients.