reet, Sacramento, Lenalidomide 404950-80-7 CA 95817. Phone: 1 916 703 0383, FAX: 1 916 703 0367, Publisher,s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript Neurobiol Dis. Author manuscript, available in PMC 2011 March 1. Published in final edited form as: Neurobiol Dis. 2010 March, 37: 549 557. doi:10.1016/j.nbd.2009.11.013.
NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript of cell cycle re entry in neurons related to pathological conditions has been further Myricetin confirmed in a number of reports, including experiments in primary neuron cultures and animal models of disease including AD, ALS, stroke, traumatic brain injury and cerebral hypoxia ischemia. Furthermore, our recent genomic and bioinformatic studies have consistently placedcell cycle as among the top ranked functional categories for gene transcripts that are altered in rats one day following any of several different types of insults to the central nervous system . These examples demonstrate aberrant cell cycle re entry as a hallmark of CNS diseases with dying neurons, and while cell cycle re entry in more commonly associated with tumor cells, there are very different consequences of this event between these tissues.
In contrast to neurons, when tumor cells re enter the cell cycle, they survive and may continue to proliferate in the presence of an oncogene. For reasons not completely understood, a mature neuron that reenters the cell cycle is neither able to advance to a new G0 quiescent state nor revert to its earlier G0 state. This presents a critical dilemma to the neuron from which death may be an unavoidable, but necessary, outcome for these mature neurons attempting to complete the cell cycle. Since re entry into the cell cycle by neurons has been associated with many diseases and linked inextricably to death, the cell cycle represents a viable target for treatments and therapies, so long as the consequences on other cell types, such as neuroprogenitor cells, are considered.
As a way to describe potential therapeutic targets, we propose the expanded cell cycle one which includes not only the traditional cell cycle proteins, but also the mitogenic molecules and the signaling pathways that interact with them. The expanded cell cycle includes some of the current targets for treating CNS diseases. It provides a composite perspective encompassing a broad range of molecules representing potential targets and thus approaches that can serve as treatments for CNS diseases by sharing a common outcome cell cycle inhibition. A detailed description of the cell cycle and its components follows before we discuss the specific interactions that neurons have with cell cycle proteins.
Classical proteins and regulators of the cell cycle The cell cycle is the series of events that lead to cell replication. In brief, the release of cells from a quiescent state results in their entry into the first gap phase, during which the cells prepare for DNA replication in the synthetic phase. This is followed by the second gap phase and mitosis phase. When cells cease proliferating, either due to the presence of specific anti mitogenic signals, or the absence of pro mitogenic signals, they exit the cycle and enter the G0 quiescent phase. A majority of types of newly divided G0 cells can re enter the cell cycle after passi