Cell Cycle Regulators Related to the Glucocorticoid Receptor

Eukaryotic cell-cycle, with the relative duration of each phase

G1/S-specific cyclin-D1 (CD1) : The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. CD1 forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb which also regulates the expression of CD1.

P21: p21 is a potent cyclin-dependent kinase inhibitor (CKI). The p21 (WAF1) protein binds to and inhibits the activity of cyclinCDK2 or –CDK4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This was a major discovery in the early 1990’s that revealed how cells stop dividing after being exposed to damaging agents such as radiation. In addition to growth arrest, p21 can mediate cellular senescence and one of the ways it was discovered was as a senescent cell-derived inhibitor. The p21(WAF1) protein can also interact with proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of apoptosis following caspase activation. However p21 may inhibit apoptosis and does not induce cell death on its own [4].

P27 or Cyclin-dependent kinase inhibitor 1B belongs to the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitor proteins. The p27 protein binds to and prevents the activation of cyclin ECDK2 or cyclin DCDK4 complexes, and thus controls the cell cycle progression at G1. It is often referred to as a cell cycle inhibitor protein because its major function is to stop or slow down the cell division cycle.  p27Kip1 binds to cyclin D either alone, or when complexed to its catalytic subunit CDK4. In doing so p27Kip1 inhibits the catalytic activity of Cdk4, which means that it prevents Cdk4 from adding phosphate residues to its principal substrate, the retinoblastoma (pRb) protein. Increased levels of the p27Kip1 protein typically cause cells to arrest in the G1 phase of the cell cycle. Likewise, p27Kip1 is able to bind other Cdk proteins when complexed to cyclin subunits such as Cyclin E/Cdk2 and Cyclin A/Cdk2.

Retinoblastoma protein (pRb): pRb prevents the cell from replicating damaged DNA by preventing its progression along the cell cycle through G1 (first gap phase) into S (synthesis phase).[7] pRb binds and inhibits transcription factors of the E2F family, which are composed of dimers of an E2F protein and a DP protein.[8] The transcription activating complexes of E2 promoter-binding–protein-dimerization partners (E2F-DP) can push a cell into S phase.[9][10][11][12][13] As long as E2F-DP is inactivated, the cell remains stalled in the G1 phase. When pRb is bound to E2F, the complex acts as a growth suppressor and prevents progression through the cell cycle [3]. The pRb-E2F/DP complex also attracts a histone deacetylase (HDAC) protein to the chromatin, reducing transcription of S phase promoting factors, further suppressing DNA synthesis.

Source: Wikipedia (links are highlighted)

This list definitely does not cover the whole range of cell-cycle modulators, which have been shown or linked with GR . Albeit, it does include some critical molecules, linked to the antiproliferative effects of glucocorticoids and I intent to gradually expand the list as I go.

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Music For the Day: Portrait of my Mother by MANOS HADJIDAKIS

Manos Hadjidakis one of the greatest Greek and world artists to have ever lived. Each piece of music he created is unique in its own way. Listening to Hadjidakis music is like viewing life through a kaleidoscope. “Portrait of My Mother” is one of my favorites. Enjoy!

Here you can find the official website of Manos Hadjidakis.

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Calcium: A Fundamental Player in Brain Development

Calcium Waves

During the stage of neurogenesis in the embryonic brain, Ca2+ plays an orchestrating role in the function and behavior of neural-stem/progenitor cells (NSPCs). Owens and Kriegstein [1] r eport in the developing rat cortex 3 groups of NSPCs  based on the patterns of spontaneous intracellular Ca2+ waves having as epicenter the cell soma. The authors note 1), single cells generating independent Ca2+ waves, 2),  pairs of cells undergoing synchronous Ca2+ fluctuations and last, 3) groups of adjacent cells undergoing coordinated Ca2+bursts. Weissman et. al. [2], report that radial glial Ca2+ waves depend on connexin hemichannels, P2Y1 ATP receptors, and intracellular IP3-mediated Ca2+ release. In addition, inhibition of  Ca2+ propagation results in impairment of proliferation. The latter is illustrated in the figure below (from [2]). The pattern, frequency and type of Ca2+ waves observed in precursor cells and differentiating neurons differs. Accordingly, NSPCs have lower frequency waves which are generated by intracellular Ca2+ release and are not dependent on neurotransmitter release [1,2]. Contrary, differentiating cells have increased frequency and duration of Ca2+ bursts resulting from voltage-dependent  L-type Ca2+ channel activation [3]. Also, intracellular Ca2+stores in differentiating neurons have ryanodine and caffeine sensitivity and baseline cytosolic Ca2+ levels  depend on Na+– Ca2+ exchange activity.

Calcium Waves "Push" NSPCs through the Cell Cycle

 

References

[1]  Owens, DF and Kriegstein, AR (1998) Patterns of Intracellular Calcium Fluctuation in Precursor Cells of the Neocortical Ventricular Zone. J.Neurosc 18(14):5374-5388

[2] Weissman TA, Riquelme PA,  Ivic L, Flint AC, Kriegstein AR (2004) Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex. Neuron 43:647–661.

[3] Maric D, Maric I, Barker JL (2000) Developmental changes in cell calcium homeostasis during neurogenesis of the embryonic rat cerebral cortex. Cereb Cortex10:561–573.

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Music of The Day: Dark night of the Soul by Philip Wesley

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January 13, 2012 · 10:29 pm