Inhibitors of phosphatidylinositol 3-kinase activity prevent cell cycle progression and induce apoptosis at the M/G1 transition in CHO cells

Recent research has demonstrated that cell cycle-associated molecules are activated in multiple forms of cell death in mature neurons, and raised a hypothesis that unscheduled cell cycle activity leads to neuronal cell death. But there is little evidence that changes in endogenous level of these molecules are causally associated with neuronal cell death. Here we transfected small interfering RNA (siRNA) targeting cyclin-dependent kinase (CDK) inhibitor p27, which plays an important role in cell cycle arrest at G1-S phase, into cultured cortical neurons. Transfection of p27 siRNA reduced neuronal viability in a time-dependent manner. p27 siRNA induced phosphorylation of retinoblastoma protein (Rb), a marker of cell cycle progression at late G1 phase. Moreover, phosphorylation of Rb and neuronal cell death provoked by p27 siRNA were abrogated by pharmacological CDK inhibitors, olomoucine and purvalanol A. Our data demonstrate that a decrease in endogenous p27 induces neuronal cell death through elevating cell cycle activity.

Section: Discussionsupporting

confidence: 67%

p27 small interfering RNA induces cell death through elevating cell cycle activity in cultured cortical neurons: a proof-of-concept study

Akashiba

Matsuki

Nishiyama

2006

“…caspase activation) and 40 % of cells were apoptosed after 3 days [5], leading to the hypothesis that there is a checkpoint early in G1 where cells decide to continue G1 and proliferation or to go into apoptosis. The mechanism behind this checkpoint might involve PI 3-kinase, an important proliferative protein for cell cycle progression, since the inhibition of this protein resulted in early G1 cell cycle arrest and increased caspase activation [148]. The notion of an early G1 checkpoint is consistent with the findings presented before of early apoptosis in neuronal and oligodendrocyte development, and this point could represent the more physiological apoptosis checkpoint that is important in development and tissue homeostasis.…”

Section: Apoptosismentioning

confidence: 54%

Cell fate determination during G1 phase progression

Blomen

Boonstra

2007

Self Cite

100

During the cell cycle, a cell may encounter one of five different fates: it can proliferate, differentiate, become quiescent or senescent, or go into apoptosis. The initiation of such fates is often seen in the G1 phase. The aim of this review is to describe an integrative model of G1 phase progression and cell fate determination. Along the G1 phase, the cell will encounter an early checkpoint after which apoptosis can result. For a quiescent state and for differentiation, the cell will exit G1 before the restriction point and a subsequent differentiation checkpoint will decide the fate of the cell, quiescence or differentiation. After the restriction point, the cell can be arrested in response to stress stimuli, such as telomere depletion, and a decision between senescence and apoptosis occurs.

“…Expression of wild-type PTEN in tumor cells containing endogenous mutant PTEN inhibits AKT activity, induces G1 cell cycle arrest, and causes apoptosis. Evidence is accumulating that inhibition of PI3K with PI3K inhibitors causes G1 growth arrest and apoptosis in different carcinoma cells and normal cells [32][33][34][35]. A recent study reported that X-radiation in combination with the PI3K inhibitor LY294002 potentiated radiation-induced human esophageal cancer cell-killing synergistically, indicating that selective inhibition of the PI3K survival signaling pathway enhanced radiosensitivity in these cells [36].…”

Section: Resultsmentioning

confidence: 99%

Unscheduled CDK1 activity in G1 phase of the cell cycle triggers apoptosis in X-irradiated lymphocytic leukemia cells

Wu¹,

Feng²,

Xie³

et al. 2006

Cyclin-dependent kinase 1 (CDK1) is a major component of the cell cycle progression engine. Recently, several investigations provided evidence demonstrating that unscheduled CDK1 activation may also be involved in apoptosis in cancerous cells. In this article, we demonstrate that X-ray irradiation induced G1 arrest in MOLT-4 lymphocytic leukemia cells, the arrest being accompanied by reduction in the activity of CDK2, but increased CDK1 activity and cell apoptosis in the G1 phase. Interestingly, this increase in CDK1 and apoptosis by ionizing radiation was prevented by pretreatment with the CDK1 inhibitor, roscovitine, suggesting that CDK1 kinase activity is required for radiation-induced apoptotic cell death in this model system. Furthermore, cyclin B1 and CDK1 were detected co-localizing and associating in G1 phase MOLT-4 cells, with the cellular lysates from these cells revealing a genotoxic stress-induced increase in CDK1 phosphorylation (Thr-161) and dephosphorylation (Tyr-15), as analyzed by postsorting immunoprecipitation and immunoblotting. Finally, X-irradiation was found to increase Bcl-2 phosphorylation in G1 phase cells. Taken together, these novel findings suggest that CDK1 is activated by unscheduled accumulation of cyclin B1 in G1 phase cells exposed to X-ray, and that CDK1 activation, at the wrong time and in the wrong phase, may directly or indirectly trigger a Bcl-2-dependent signaling pathway leading to apoptotic cell death in MOLT-4 cells.