Abstract
Cell cycle regulation is essential for the development of multicellular organisms, but many cells in adulthood, including neurons, exit from cell cycle. Although cell cycle-related proteins are suppressed after cell cycle exit in general, recent studies have revealed that growth arrest triggers extra-cell cycle regulatory function (EXCERF) in some cell cycle proteins, such as p27(kip1), p57(kip2), anaphase-promoting complex/cyclosome (APC/C), and cyclin E. While p27 is known to control G1 length and cell cycle exit via inhibition of cyclin-dependent kinase (CDK) activities, p27 acquires additional cytoplasmic functions in growth-arrested neurons. Here, we introduce the EXCERFs of p27 in post-mitotic neurons, mainly focusing on its actin and microtubule regulatory functions. We also show that a small amount of p27 is associated with the Golgi apparatus positive for Rab6, p115, and GM130, but not endosomes positive for Rab5, Rab7, Rab8, Rab11, SNX6, or LAMTOR1. p27 is also colocalized with Dcx, a microtubule-associated protein. Based on these results, we discuss here the possible role of p27 in membrane trafficking and microtubule-dependent transport in post-mitotic cortical neurons. Collectively, we propose that growth arrest leads to two different fates in cell cycle proteins; either suppressing their expression or activating their EXCERFs. The latter group of proteins, including p27, play various roles in neuronal migration, morphological changes and axonal transport, whereas the re-activation of the former group of proteins in post-mitotic neurons primes for cell death.
Highlights
Cell cycle regulation is fundamental for normal development and homeostasis in multicellular organisms
Many cyclin-dependent kinase (CDK), including Cdk1, 2, and 4, are activated via binding to cyclins, Extra-Cell Cycle Regulatory Function of p27 whereas Cdk5 is mainly activated by p35 and p39 (Kawauchi, 2014)
Thr187 phosphorylation of p27 is observed in cortical neurons (Kawauchi et al, 2006), it is unclear which kinase(s) contributes to this phosphorylation in post-mitotic neurons, where Cdk2 activity is low
Summary
Cell cycle regulation is fundamental for normal development and homeostasis in multicellular organisms. Like the other cip/kip proteins, p27kip (hereafter, p27) binds to a cyclin-CDK complex to suppress the kinase activity of CDKs in general, p27 does not inhibit the Cyclin D-Cdk complex in proliferating cells, where the Cyclin D/Cdk enhances the phosphorylation of p27 at Tyr, resulting in its degradation (Chu et al, 2007; Grimmler et al, 2007; James et al, 2008; Ou et al, 2011). Thr187 phosphorylation of p27 is observed in cortical neurons (Kawauchi et al, 2006), it is unclear which kinase(s) contributes to this phosphorylation in post-mitotic neurons, where Cdk activity is low In addition to these kinases, it has been reported that connexin-43 (Cx43), a component of the gap junction, acts as an upstream regulator of p27. The observation of p27-mediated microtubule regulation in lipid raft trafficking in non-neuronal cells may be consistent with in vivo function of p27 and caveolin-1 in immature neurons in the developing cerebral cortex
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