Dynamic Changes of p27kip1 and Skp2 Expression in Injured Rat Sciatic Nerve

Shen, Aiguo; Shi, Shuxian; Chen, Meng‐Ling; Qin, Jing; Gao, Shangfeng; Cheng, Chun

doi:10.1007/s10571-007-9167-8

Cited by 8 publications

(8 citation statements)

References 26 publications

(26 reference statements)

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“…However, we found that suppression of p57kip2 leads to cell cycle exit. This can be explained by the observed induction of the related CKIs p27kip1 and p21cip1 and is in accordance with previously published results (25,26). Currently we have no evidence that the members of the INK4 family, namely p15, p16, p18, and p19, are involved in regulating Schwann cell cycle exit in response to p57kip2 suppression.…”

Section: Discussionsupporting

confidence: 92%

The cyclin-dependent kinase inhibitor p57kip2 is a negative regulator of Schwann cell differentiation and in vitro myelination

Heinen

Kremer²,

Göttle³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The p57kip2 gene encodes a member of the cyclin-dependent kinase inhibitor family, proteins known to block G 1/S transition during the mammalian cell cycle. We observed that expression of p57kip2 in Schwann cells of the developing and injured adult peripheral nervous system is dynamically regulated. Using gene knockdown by means of vector-based RNA interference in cultured primary Schwann cells we found that reduced levels of p57kip2 lead to cell cycle exit, actin filament stabilization, altered cell morphology and growth, and down-regulation of promyelinating markers as well as induction of myelin genes and proteins. In addition, we could demonstrate that in vitro myelination is enhanced by p57kip2-suppressed Schwann cells. Using microarray technology we found that these cellular reactions are specific to lowered p57kip2 expression levels and detected a shift of the transcriptional expression program toward the pattern known from Schwann cells in developing peripheral nerves. Because in the absence of axons primary Schwann cells normally do not display differentiation-associated reactions, we conclude that we have identified a mechanism and an important intrinsic negative regulator of myelinating glia differentiation.glia ͉ immune neuropathies ͉ myelin ͉ peripheral nerve A xons are tightly associated with myelinating glial cells in the vertebrate nervous system, Schwann cells in the peripheral nervous system, and oligodendrocytes in the CNS. These cells wrap around axons in a radial growth and migration process and establish multiple lipid-and protein-rich layers to support and electrically insulate them, thus enabling saltatory propagation of electrical signals. As a result of axonal segregation, myelinating Schwann cells are associated with large-caliber axons in a 1:1 relationship and represent highly specialized and differentiated cells. Schwann cells derive from neural crest, and their differentiation during peripheral nerve development was shown to depend on a variety of genes, such as integrins, the transcription factors Sox10, Oct-6, and Krox20, or neuregulin-, p75-LNGFR, and Lgi4 signaling cascades (1-7).Cell cycle exit is a prerequisite for myelinating glial cell differentiation followed by morphological changes as well as the expression and deposition of myelin proteins within the layers of lipid sheaths. The establishment of such a complex morphology depends on regulated cytoskeletal dynamics, e.g., actin filament turnover. This was demonstrated by means of application of cytochalasin D, a mycotoxin that interferes with actin filament assembly. Differentiation and myelination of Schwann cells cocultured with dorsal root ganglion (DRG) neurons were found to be blocked when this drug was added to the culture medium, indicating that actin filament dynamics is imperative for Schwann cell growth and morphological adaptation during the myelination process (8). Nevertheless, the question as to whether naturally occurring regulators of cytoskeletal dynamics, acting during nerve development and/or after inju...

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Section: Discussionsupporting

confidence: 92%

The cyclin-dependent kinase inhibitor p57kip2 is a negative regulator of Schwann cell differentiation and in vitro myelination

Heinen

Kremer²,

Göttle³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…p27 kip1 has been implicated in promoting cell cycle arrest of neural progenitors during embryogenesis [6,7], in regulating the division of transit amplifying progenitors in the adult subventricular zone [8]. These data confirmed the effect of p27 kip1 on central nervous system (CNS) development, and we recently reported its expression in injured sciatic nerve [9] and injured spinal cord [10]. FKHRL1 (FOXO3a), which is a forkhead transcription factor of the forkhead box, class O (FOXO) subfamily, is a target of phosphatidylinositol 3-kinase (PI3-K) signaling, which regulates their activity via phosphorylation mediated by protein kinase B/Akt and serum and glucocorticoidinduced kinase (SGK) [11].…”

Section: Introductionsupporting

confidence: 64%

“…p27 kip1 , as a member of Cip/Kip family of cyclindependent kinase inhibitors, plays an important role in cell cycle regulation and neurogenesis in the developing CNS. We recently reported p27 kip1 was down-regulated in the injured sciatic nerve [9] and the lumbar spinal cord after sciatic nerve injury [28], and the down-regulation of p27 kip1 was very likely to be involved in the regeneration process after peripheral nerve injury. Previous studies showed down-regulated p27 kip1 through FOXO transcriptional inhibition was associated with multitude cell types proliferation, including hematopoietic cells [13], tumour cell strains [14], T cells [15] and endothelial cells [29,30].…”

Section: Discussionmentioning

confidence: 98%

Peripheral Nerve Injury Induces Down-Regulation of Foxo3a and p27kip1 in Rat Dorsal Root Ganglia

et al. 2008

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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.

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“…Pirh2 Expression is Up-regulated after Brain Injury and Inversely Correlated with p27 kip1 Expression Previous study conducted by our group has shown that p27 kip1 expression was reduced during the repair process after injury in nerve system (Liu et al 2010;Shen et al 2008). Western blot and immunohistochemistry were performed to investigate the changes of Pirh2 and p27 kip1 after brain injury.…”

Section: Resultsmentioning

confidence: 99%

“…In the central nervous system (CNS), p27 kip1 plays important roles in promoting cell cycle arrest of neural progenitors during embryogenesis (Carruthers et al 2003;Miyazawa et al 2000), regulating the division of transit amplifying progenitors in the adult subventricular zone (Doetsch et al 2002) and influencing neuronal differentiation and neuronal migration in the cerebral cortex (Nguyen et al 2006). Moreover, previous study showed that p27 kip1 expression was reduced during the repair process after injury in adult brain, spinal cord and dorsal root ganglia (Liu et al 2010;Shen et al 2008).…”

Section: Introductionmentioning

confidence: 95%

Changes in Pirh2 and p27kip1 Expression Following Traumatic Brain Injury in Adult Rats

Shi

Zhao

et al. 2011

J Mol Neurosci

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Pirh2, a p53-induced ubiquitin-protein ligase, has been reported to promote ubiquitin-dependent degradation of p27(kip1), which plays an essential role in mammalian cell cycle regulation and neurogenesis in the developing central nervous system (CNS). However, their distributions and functions in the nervous system lesion and repair remain unclear. In this study, we observed that the up-regulated expression of Pirh2 was concomitant with decreased p27(kip1) level after traumatic brain injury by Western blot and immunohistochemistry. Immunofluorescence double-labeling revealed that Pirh2 was mainly co-expressed with GFAP and CD11b. Meanwhile, we also examined the expression profiles of proliferating cell nuclear antigen (PCNA) whose changes were correlated with the expression of Pirh2. In addition, Pirh2 colocalized with p27(kip1) and PCNA. Immunoprecipitation further showed that they interacted with each other in the pathophysiology process. In summary, our data indicated Pirh2 might be a negative regulator of p27(kip1) and associated with glial proliferation.

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Dynamic Changes of p27kip1 and Skp2 Expression in Injured Rat Sciatic Nerve

Cited by 8 publications

References 26 publications

The cyclin-dependent kinase inhibitor p57kip2 is a negative regulator of Schwann cell differentiation and in vitro myelination

The cyclin-dependent kinase inhibitor p57kip2 is a negative regulator of Schwann cell differentiation and in vitro myelination

Peripheral Nerve Injury Induces Down-Regulation of Foxo3a and p27kip1 in Rat Dorsal Root Ganglia

Changes in Pirh2 and p27kip1 Expression Following Traumatic Brain Injury in Adult Rats

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