Myelinated fibers are organized into distinct domains that are necessary for saltatory conduction. These domains include the nodes of Ranvier and the flanking paranodal regions where glial cells closely appose and form specialized septate-like junctions with axons. These junctions contain a Drosophila Neurexin IV-related protein, Caspr/Paranodin (NCP1). Mice that lack NCP1 exhibit tremor, ataxia, and significant motor paresis. In the absence of NCP1, normal paranodal junctions fail to form, and the organization of the paranodal loops is disrupted. Contactin is undetectable in the paranodes, and K(+) channels are displaced from the juxtaparanodal into the paranodal domains. Loss of NCP1 also results in a severe decrease in peripheral nerve conduction velocity. These results show a critical role for NCP1 in the delineation of specific axonal domains and the axon-glia interactions required for normal saltatory conduction.
Recent studies identified a short peptide motif that serves as a docking site for cyclin͞cyclin-dependent kinase (cdk) 2 complexes . Peptides containing this motif block the phosphorylation of substrates by cyclin A͞cdk2 or cyclin E͞cdk2. Here we report that cell membrane-permeable forms of such peptides preferentially induced transformed cells to undergo apoptosis relative to nontransformed cells. Deregulation of E2F family transcription factors is a common event during transformation and was sufficient to sensitize cells to the cyclin͞cdk2 inhibitory peptides. These results suggest that deregulation of E2F and inhibition of cdk2 are synthetically lethal and provide a rationale for the development of cdk2 antagonists as antineoplastic agents.Certain molecular pathways frequently are altered during human carcinogenesis. Therefore one approach to treating cancer, while minimizing host toxicity, would be to develop drugs that preferentially kill cells in which such pathways are altered.An example of a molecular pathway that is recurrently altered in cancer involves the retinoblastoma tumor suppressor protein (pRB) (1-3). Many tumors lack a wild-type RB-1 allele, thus depriving them of pRB. Furthermore, pRB is negatively regulated by cyclin-dependent kinases (cdks). These cdks are, in turn, negatively regulated by certain cdk inhibitors and positively regulated by certain cyclins. These upstream pRB regulators frequently are altered in tumors that retain a wild-type RB-1 allele. Thus, functional inactivation of pRB, a known inhibitor of cell growth, may be a necessary step in human carcinogenesis.Members of the E2F cell-cycle regulatory transcription factor family are critical downstream targets of pRB. Binding to pRB converts E2F from a transcriptional activator to a potent transcriptional repressor. Consequently, E2F-responsive genes are activated in cancer cells because of loss of pRB͞E2F repressor complexes and liberation of free, transcriptionally active E2F. Of note, at least some E2F family members, including E2F1, are themselves transcribed from E2F-responsive promoters (4-7). Thus, pathological activation of E2F responsive genes can establish a positive feedback loop. Paradoxically, forced activation of E2F-responsive genes, such as through the overproduction of E2F1, can induce both cellular proliferation and cell death (apoptosis) (8-11).E2F family members bind to DNA as heterodimers with members of the DP family. The DNA-binding capability of some of these heterodimers is negatively regulated by cyclin A͞cdk2 (12-15). For example, E2F1, E2F2, and E2F3 each contain a short, collinear cyclin A͞cdk2 binding motif that is required for the timely neutralization of E2F DNA-binding capability as cells traverse and prepare to exit S phase (13,16,17). Mutation of this motif in E2F1 enhances its ability to induce apoptosis (13). In summary, E2F is negatively regulated by both pRB and cyclin A͞cdk2. We therefore reasoned that pharmacologic inhibition of cyclin A͞cdk2 might preferentially kill cells in whic...
The node of Ranvier is a distinct domain of myelinated axons that is highly enriched in sodium channels and is critical for impulse propagation. During development, the channel subtypes expressed at the node undergo a transition from Nav1.2 to Nav1.6. Specialized junctions that form between the paranodal glial membranes and axon flank the nodes and are candidates to regulate their maturation and delineate their boundaries. To investigate these roles, we characterized node development in mice deficient in contactin-associated protein (Caspr), an integral junctional component. Paranodes in these mice lack transverse bands, a hallmark of the mature junction, and exhibit progressive disruption of axon-paranodal loop interactions in the CNS. Caspr mutant mice display significant abnormalities at central nodes; components of the nodes progressively disperse along axons, and many nodes fail to mature properly, persistently expressing Nav1.2 rather than Nav1.6. In contrast, PNS nodes are only modestly longer and, although maturation is delayed, eventually all express Nav1.6. Potassium channels are aberrantly clustered in the paranodes; these clusters are lost over time in the CNS, whereas they persist in the PNS. These findings indicate that interactions of the paranodal loops with the axon promote the transition in sodium channel subtypes at CNS nodes and provide a lateral diffusion barrier that, even in the absence of transverse bands, maintains a high concentration of components at the node and the integrity of voltage-gated channel domains.
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