Inhibition of Chk1 by Activated PKB/Akt

King, Frank W.; Skeen, Jennifer; Hay, Nissim; Shtivelman, Emma

doi:10.4161/cc.3.5.894

Cited by 72 publications

(76 citation statements)

References 18 publications

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“…In response to DNA damage during the G2 phase, Akt/PKB was also reported to induce Chk1 phosphorylation at Ser280 (King et al, 2004;Shtivelman et al, 2002) and to reduce nuclear localization of Chk1 (Puc et al, 2005). However, the in vitro analysis reveals that Akt/PKB phosphorylates Chk1 at several sites, among which Ser280 is only a minor phosphorylation site .…”

Section: Chk1 Phosphorylation At Ser280mentioning

confidence: 91%

Novel Insights into Chk1 Regulation by Phosphorylation

Kasahara

Inagaki

2015

Cell Struct. Funct.

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ABSTRACT. Checkpoint kinase 1 (Chk1) is a conserved protein kinase central to the cell-cycle checkpoint during DNA damage response (DDR). Until recently, ATR, a protein kinase activated in response to DNA damage or stalled replication, has been considered as the sole regulator of Chk1. Recent progress, however, has led to the identification of additional protein kinases involved in Chk1 phosphorylation, affecting the subcellular localization and binding partners of Chk1. In fact, spatio-temporal regulation of Chk1 is of critical importance not only in the DDR but also in normal cell-cycle progression. In due course, many potent inhibitors targeted to Chk1 have been developed as anticancer agents and some of these inhibitors are currently in clinical trials. In this review, we summarize the current knowledge of Chk1 regulation by phosphorylation.

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Section: Chk1 Phosphorylation At Ser280mentioning

confidence: 91%

Novel Insights into Chk1 Regulation by Phosphorylation

Kasahara

Inagaki

2015

Cell Struct. Funct.

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“…In MDCK cells LY-294002 triggers apoptosis and G2 arrest, which is inhibited by AKT-mediated phosphorylation of Chk-1 on site Ser 280 leading to inhibition of Chk-1. 34,35 In hematopoietic cells inhibition of GSK3 kinase that is a kinase negatively regulated by Akt, leads to enhancement of Chk-1 (Ser 345) phosphorylation. 36 Etoposide treatment of these hematopoietic cells induces G2/M arrest in an Akt-and Chk-1-dependent manner indicating that in these cells increased Akt activity and the correlating increase in phosphorylation of Chk-1 stimulate G2 arrest.…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

Hemström

Sandström

Zhivotovsky

2006

Intl Journal of Cancer

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Non-small cell lung cancer cells (NSCLC) are more resistant to anticancer treatment as compared with other types of cancer cells. Recently (Hemstr€ om et al., Exp Cell Res 2005;305:200-13) we showed that apoptosis of U1810 NSCLC cells induced by the staurosporine analog PKC 412 correlated with inhibition of Akt and ERK1/2, suggesting the involvement of these kinases in cell survival. Here we investigated the contribution of the PI3-kinase/Akt and MEK/ERK pathways to survival of NSCLC cells. The two signaling pathways were studied by using different combinations of the PI3-kinase inhibitors LY-294002 and wortmannin, the Akt activator Ro 31-8220, the MEK inhibitor PD 98059 and PKC 412. PI3-kinase inhibitors induced apoptosis-like death in U1810 cells. H157 cells in general were relatively resistant to PI3 kinase/Akt inhibitors yet these compounds sensitized cells to the DNA-damaging drug VP-16, while Ro 31-8220 could not. PD 98059 only had a sensitizing effect on H157 cells when combined with PI3-kinase inhibition and VP-16. Key words: mitotic catastrophe; non-small cell lung carcinoma; PI3-kinase; Akt; apoptosis Cell lines derived from non-small cell lung carcinoma (NSCLC) are most often characterized by cellular resistance towards anticancer drugs and radiation. 1 Efficiency of action of DNA-damaging drugs used in anticancer therapy depends on the successful ability to induce growth arrest and to activate the cell death machinery. 2 Apoptosis induced by DNA damage is typically associated with activation of a family of proteases, the caspases, as a result of a sequence of mitochondria-mediated events. The caspases cleave many proteins, eventually leading to biochemical and morphological apoptosis-specific changes. In addition to activation of the caspases, mediated by release of cytochrome c, several proteins, such as apoptosis inducing factor (AIF) and endonuclease G are also released from mitochondria, translocate to the nuclei and induce chromatin condensation and cell death independently of caspases.Cell cycle regulation is also an important determinant for efficiency of cell death in response to DNA damage. For example, topoisomerase inhibitors are suggested to be particularly effective in S-phase when DNA replication occurs, 3 while irradiated cells are most sensitive at G2/M phase. 4 DNA-damaged cells are removed by cell death following activation of the DNA damage checkpoints in G1 and G2-phases of the cell cycle. 5 There are many mechanisms for cells being resistant to DNA damage. 6 For example, resistant lung cancer cells have an increased activity of DNAdependent protein kinase (DNA-PK) and DNA repair, correlating with a decreased incidence of cell death, suggesting involvement of DNA-PK in tumor survival. 7,8 Aberrant signaling of other kinases, such as the Ras/MEK/ERK and PI3-kinase/Akt pathways is also contributes to cell death resistance. In NSCLC-patients phospho-Akt overexpression confers a stage-independent survival disadvantage 9 and in NSCLC cell lines a high activity of Akt promotes cellular...

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“…An intriguing function of Akt/PKB is its role in mediating bypass of the G2/ M checkpoint activated in response to genotoxic damage [182], which stems, at least in part, from the ability of Akt/PKB to mitigate DNA damage-dependent inhibition of Cdk1 [182]. The molecular mechanism underlying resistance of Cdk1 to inhibition by genotoxic agents in cells expressing activated Akt/PKB is not known, though evidence that Akt/PKB-dependent phosphorylation of Chk1 at S 280 renders the latter apparently refractive to activation by ATM/ATR may provide an answer [183]. Considering that phosphorylation-dependent inhibition of the E3 ligase responsible for Plk1 degradation is controlled by Akt/ PKB and results in stabilization and reactivation of Plk1 [184], and this is eventually necessary to recover from DNA damage [101], this could represent another level at which Akt/PKB participates in reinforcing the loop controlling Cdk1 activity [185].…”

Section: Other Protein Kinases Affecting the Onset Of Mitosismentioning

confidence: 99%

Protein kinases controlling the onset of mitosis

Ferrari

2006

Cell. Mol. Life Sci.

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Abstract. This review article focuses on protein kinases regulating the onset and transition through mitosis. The essay begins by introducing the structural features of the protein kinase catalytic domain and emphasizing the mechanism of enzymatic activation of this class of proteins. Next follows a short historical perspective on cell division and a description of our current understanding of mitosis. In the central part of the review I examine the four major kinases that set the stage for mitosis, which

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Inhibition of Chk1 by Activated PKB/Akt

Cited by 72 publications

References 18 publications

Novel Insights into Chk1 Regulation by Phosphorylation

Novel Insights into Chk1 Regulation by Phosphorylation

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

Protein kinases controlling the onset of mitosis

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