Twice switched at birth: Cell cycle-independent roles of the “neuron-specific” cyclin-dependent kinase 5 (Cdk5) in non-neuronal cells

2011 ◽  
Vol 23 (11) ◽  
pp. 1698-1707 ◽  
Author(s):  
Johanna Liebl ◽  
Robert Fürst ◽  
Angelika M. Vollmar ◽  
Stefan Zahler
Keyword(s):  
Cell Cycle ◽  
Neuronal Cells ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase 5

scholarly journals Interplay between MEK-ERK signaling, cyclin D1, and cyclin-dependent kinase 5 regulates cell cycle reentry and apoptosis of neurons

2012 ◽  
Vol 23 (18) ◽  
pp. 3722-3730 ◽  
Author(s):  
Prashant Kumar Modi ◽  
Narayana Komaravelli ◽  
Neha Singh ◽  
Pushkar Sharma
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Molecular Mechanisms ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Amyloid Peptide ◽  
Erk Signaling ◽  
Cyclin Dependent Kinase ◽  
Cell Cycle Reentry ◽  
Cyclin Dependent Kinase 5

In response to neurotoxic signals, postmitotic neurons make attempts to reenter the cell cycle, which results in their death. Although several cell cycle proteins have been implicated in cell cycle–related neuronal apoptosis (CRNA), the molecular mechanisms that underlie this important event are poorly understood. Here, we demonstrate that neurotoxic agents such as β-amyloid peptide cause aberrant activation of mitogen-activated kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) signaling, which promotes the entry of neurons into the cell cycle, resulting in their apoptosis. The MEK-ERK pathway regulates CRNA by elevating the levels of cyclin D1. The increase in cyclin D1 attenuates the activation of cyclin-dependent kinase 5 (cdk5) by its neuronal activator p35. The inhibition of p35-cdk5 activity results in enhanced MEK-ERK signaling, leading to CRNA. These studies highlight how neurotoxic signals reprogram and alter the neuronal signaling machinery to promote their entry into the cell cycle, which eventually leads to neuronal cell death.

scholarly journals Cyclin-Dependent Kinase 5 Differentially Regulates the Transcriptional Activity of the Glucocorticoid Receptor through Phosphorylation: Clinical Implications for the Nervous System Response to Glucocorticoids and Stress

2007 ◽  
Vol 21 (7) ◽  
pp. 1552-1568 ◽  
Author(s):  
Tomoshige Kino ◽  
Takamasa Ichijo ◽  
Niranjana D. Amin ◽  
Sashi Kesavapany ◽  
Yonghong Wang ◽  
...  
Keyword(s):  
Nervous System ◽  
Glucocorticoid Receptor ◽  
Transcriptional Activity ◽  
Biological Activities ◽  
Neuronal Cells ◽  
System Response ◽  
Cyclin Dependent Kinase ◽  
Proteolytic Fragment ◽  
End Effectors ◽  
Cyclin Dependent Kinase 5

Abstract Glucocorticoids, major end effectors of the stress response, play an essential role in the homeostasis of the central nervous system and influence diverse functions of neuronal cells. We found that cyclin-dependent kinase 5 (CDK5), which plays important roles in the morphogenesis and functions of the nervous system and whose aberrant activation is associated with development of neurodegenerative disorders, interacted with the ligand-binding domain of the glucocorticoid receptor (GR) through its activator p35 or its active proteolytic fragment p25. CDK5 phosphorylated GR at multiple serines, including Ser203 and Ser211 of its N-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to DNA. In microarray analyses using rat cortical neuronal cells, the CDK5 inhibitor roscovitine differentially regulated the transcriptional activity of the GR on more than 90% of the endogenous glucocorticoid-responsive genes tested. Thus, CDK5 exerts some of its biological activities in neuronal cells through the GR, dynamically modulating GR transcriptional activity in a target promoter-dependent fashion.

scholarly journals Cyclin I-like (CCNI2) is a cyclin-dependent kinase 5 (CDK5) activator and is involved in cell cycle regulation

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Chengcheng Liu ◽  
Xiaoyan Zhai ◽  
Bin Zhao ◽  
Yanfei Wang ◽  
Zhigang Xu
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Mitotic Cell ◽  
Cyclin Dependent Kinase ◽  
Cellular Events ◽  
Cycle Regulation ◽  
Cyclin Dependent Kinase 5 ◽  
Cyclin I

Abstract In contrast to conventional cyclin-dependent kinases that are important for mitotic cell division, cyclin-dependent kinase 5 (CDK5) is predominantly activated in post-mitotic cells and is involved in various cellular events. The kinase activity of CDK5 is tightly regulated by specific activators including p35, p39, and cyclin I (CCNI). Here we show that cyclin I-like (CCNI2), a homolog of CCNI, interacts with CDK5 and activates the kinase activity of CDK5. Different from CCNI, which colocalizes with CDK5 in the nuclei in transfected cells, CCNI2 mainly retains CDK5 in the cytoplasm as well as on the cell membrane. Furthermore, although the expression level of CCNI2 mRNA and CCNI2 protein do not change significantly during cell cycle, depletion of CCNI2 with siRNA affects cell cycle progression as well as cell proliferation. In conclusion, our data strongly suggest that CCNI2 is a novel CDK5 activator and is involved in cell cycle regulation.

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