ng specified checkpoints, whereas some types of cells, such as neurons, cannot. Because such a large number of molecules involved in the cell cycle have been discovered and characterized, we will provide a brief overview of these below. Cyclin dependent kinases and cyclins Cyclin dependent kinases Lapatinib 388082-77-7 are a group of serine/threonine kinases that form active heterodimeric complexes following binding to their regulatory subunits, cyclins. There are two main families of cyclins: mitotic cyclins and G1 cyclins . Several Cdks mainly Cdk4, Cdk6, Cdk2, Cdk1, and possibly Cdk3 cooperate to drive Liu et al. Page 2 Neurobiol Dis. Author manuscript, available in PMC 2011 March 1. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript cells through the cell cycle.
For example, Cdk4 and Cdk6 form active complexes with the D type cyclins, which are thought to Piroxicam be involved in early G1. The complexes of Cdk2 with cyclins E1 and E2 are required to complete G1 and initiate S phase, whereas Cdk2 with cyclin A control S/G transition. Translocation of cyclin B with Cdk1 from cytoplasm into the nucleus heralds the onset of mitosis, and the destruction of cyclin B is required for exit from mitosis. The role of Cdk3 is still obscure, mainly due to its low expression levels. Cyclin dependent kinase inhibitors There are two subclasses of cyclin dependent kinase inhibitors the Ink4 family that prevents the formation of cyclin/Cdk complexes, and the Cip/Kip family that inhibits the kinase activity of the already formed cyclin/cdk complexes.
Thus, these inhibitors regulate the cell cycle via assessing damage and arresting progress at any of several defined checkpoints. Cdk substrates The primary substrates of Cdk4/6 and Cdk2 in G1 progression are members of the retinoblastoma protein family, including p107 and p130. Rb family members are phosphorylated by activated Cdk4/6/cyclin D and Cdk2/cyclin E complexes. The pRb is released from the transcription factor complex E2F/DP, which then activates genes required for transition to the S phase. Cell cycle re entry in post mitotic neurons results in death Under physiological conditions, neurons are subjected to a variety of stimuli and signals. These include mitogenic signals that promote re entry into the cell cycle, and also a series of antimitogenic factors that strive to maintain the neuron at rest.
However once brain injuries occur, this balance is lost. For example, some cell cycle proteins are produced in mature neurons very soon after experimental rat brain ischemia. In addition, expression of cell cycle proteins was also observed in the brains of AD patients who had mild cognitive impairment, and 6 8 months before the onset of amyloid beta deposition in the A precursor protein transgenic mouse models of AD. These findings suggest that the initiation of cell cycle protein expression is an early event in these disease processes that may eventually lead to the death of mature neurons. However, the expression of cell cycle proteins is not always associated with cell cycle re entry by neurons.
Recent studies have demonstrated that some core cell cycle proteins serve diverse post mitotic functions that span various developmental stages of a neuron, including neuronal migration, axonal elongation, axonal pruning, dendrite morphogenesis, and synaptic maturation and plasticity. Additionally, we, and others, have observed sporadic expression of cyclin D in unperturbed normal primary neurons, but there was no active Cdk4 detected in those neurons. Since G0/G1 transition is dependent on cyclin D/Cdk4 complex formation, cyclin D expression without active Cdk4 means that the control neurons could not re enter the cell cycle. When subjected to a mitogenic stimulus like thrombin, the neurons did re enter