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ABSTRACT: SCY1-like 1 binding protein 1 (SCYL1BP1) is a newly identified transcriptional activator domain containing protein with many unknown biological functions. Recently, emerging evidence reveals that it is a novel regulator of the p53 pathway, which is required for neurite outgrowth and regeneration. Here, we presented evidence to show that SCYL1BP1 inhibited NGF-mediated neurite outgrowth in PC12 cells and affected morphogenesis of primary cortical neurons by strongly decreasing p53 protein level in vitro, all of which depends on SCYL1BP1's transcriptional activator domain. Meanwhile, exogenous p53 could rescue neurite outgrowth and neuronal morphogenesis defects caused by SCYL1BP1. Furthermore, SCYL1BP1 could directly induce Mdm2 transcription, while inhibiting the function of Mdm2 by specific siRNAs resulted in partial rescue of neurite outgrowth and neuronal morphogenesis defects induced by SCYL1BP1. In vivo experiments showed that SCYL1BP1 could also depress axonal regeneration, while inhibiting the function of SCYL1BP1 by specific shRNA enhanced it. Together, these data strongly suggested that SCYL1BP1 was a novel transcriptional activator in neurite outgrowth by directly modulating Mdm2/p53-dependent pathway, which might play important roles in CNS development and axonal regeneration after injury.
Molecular biology of the cell 10/2012; · 5.98 Impact Factor
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Yonghua Liu,
Youhua Wang,
Chun Cheng, Ying Chen,
Shuxian Shi,
Jing Qin,
Feng Xiao,
Dan Zhou,
Mudan Lu,
Qiuyan Lu,
Aiguo Shen
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ABSTRACT: S-phase-associated kinase protein-2 (Skp2) is involved in ubiquitination and proteasome-mediated degradation of p27(kip1), which plays an important role in mammalian cell-cycle regulation and neurogenesis in the developing central nervous system. To investigate their expression and function in central nervous system injury and repair, we used a brain-penetrating injury model in adult rats. Western blot analysis showed a significant downregulation of p27(kip1) and a concomitant upregulation of Skp2 following brain injury, and their expression profiles were temporally correlative (r = -0.910, p = 0.037). Immunofluorescence double-labeling revealed that p27(kip1) was highly expressed in neurons (51%), astrocytes (72%), and microglia (76%) in the sham group, while its expression was decreased prominently in microglia (26%) and astrocytes (32%) at 3 days after injury. Meanwhile, Skp2 expression was very low in all cell types in the sham group; however, 3 days after injury, its expression was increased significantly in microglia (51%) and astrocytes (31%) (p < 0.001), and less significantly in neurons (8%) (p = 0.038), and the astrocytes and microglia had proliferated. We also examined the expression profiles of CDK2, threonine-187 phosphorylated p27(kip1), proliferating cell nuclear antigen (PCNA), and Ki67, and their changes correlated with the expression profiles of p27(kip1) and Skp2. Moreover, co-immunoprecipitation data suggested that the protein-protein interactions between p27(kip1) and Skp2 were enhanced after injury. Taken with results of previous reports, we hypothesize the Skp2 is related to the downregulation of p27(kip1) expression after brain injury, and such an event may be associated with glial proliferation, including that of astrocytes and microglia.
Journal of neurotrauma 10/2009; 27(2):361-71. · 4.25 Impact Factor
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ABSTRACT: Spy1, as a member of the Speedy/RINGO family and a novel activator of cyclin-dependent kinases, was shown to promote cell cycle progression and cell survival in response to DNA damage. While its expression and roles in nervous system lesion and repair were still unknown. Here, we performed an acute sciatic nerve injury model in adult rats and studied the dynamic changes of Spy1 expression in lumbar spinal cord. Temporally, Spy1 expression was increased shortly after sciatic nerve crush and peaked at day 2. Spatially, Spy1 was widely expressed in the lumbar spinal cord including neurons and glial cells. While after injury, Spy1 expression was increased predominantly in astrocytes and microglia, which were largely proliferated. Moreover, there was a concomitant up-regulation of CDK2 activity and down-regulation of p27. Collectively, we hypothesized peripheral nerve injury induced an up-regulation of Spy1 in lumbar spinal cord, which was associated with glial proliferation.
Cellular and Molecular Neurobiology 01/2009; 29(3):403-11. · 1.97 Impact Factor
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ABSTRACT: FOXO3a, as a forkhead transcription factor, can control cell cycle through transcriptionally down-regulating p27(kip1) level, which is a key regulator of the mammalian cell cycle and a good candidate to regulate multiple aspects of neurogenesis. To elucidate their expression and function in nervous system lesion and repair, we performed an acute sciatic nerve crush model and studied differential expressions of Foxo3a and p27(kip1) in lumbar dorsal root ganglia. Temporally, Foxo3a protein level was reduced 1 day after injury, and following Foxo3a down-regulation, p27(kip1) mRNA and protein levels were also decreased after injury. Spatially, decreased levels of Foxo3a and p27(kip1) were predominant in neurons and glial cells, which were regenerating axons and largely proliferated after injury, respectively. Together with previous reports, we hypothesized decreased levels of Foxo3a and p27(kip1) in lumbar dorsal root ganglia were implicated in axonal regeneration and the proliferation of glial cells after sciatic nerve injury.
Neurochemical Research 10/2008; 34(5):891-8. · 2.24 Impact Factor
