A Role for G1/S Cyclin-dependent Protein Kinases in the Apoptotic Response to Ionizing Radiation

Finkielstein, Carla V.; Chen, Lin G.; Maller, James L.

doi:10.1074/jbc.m206184200

Cited by 27 publications

(36 citation statements)

References 58 publications

(38 reference statements)

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“…2D). Cleavage of cyclin A to a nondegradable fragment (33) has been reported to play a role in apoptosis (34). Cleavage of cyclin-dependent kinase inhibitors p27 and p21 in apoptotic cells has also been reported (35).…”

Section: Ras-induced Apoptosis Ismentioning

confidence: 99%

Ras Triggers Ataxia-telangiectasia-mutated and Rad-3-related Activation and Apoptosis through Sustained Mitogenic Signaling

Fikaris

Lewis²,

Abulaiti

et al. 2006

Journal of Biological Chemistry

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Genetic evidence indicates that Ras plays a critical role in the initiation and progression of human thyroid tumors. Paradoxically, acute expression of activated Ras in normal rat thyroid cells induced deregulated cell cycle progression and apoptosis. We investigated whether cell cycle progression was required for Ras-stimulated apoptosis. Ras increased CDK-2 activity following its introduction into quiescent cells. Apoptotic cells exhibited a sustained increase in CDK-2 activity, accompanied by the loss of CDK-2-associated p27. Blockade of Ras-induced CDK-2 activity and S phase entry via overexpression of p27 inhibited apoptosis. Inactivation of the retinoblastoma protein in quiescent cells through expression of HPV-E7 stimulated cell cycle progression and apoptosis, indicating that deregulated cell cycle progression is sufficient to induce apoptosis. Ras failed to induce G 1 phase growth arrest in normal rat thyroid cells. Rather, Ras-expressing thyroid cells progressed into S and G 2 phases and evoked a checkpoint response characterized by the activation of ATR. Ras-stimulated ATR activity, as evidenced by Chk1 and p53 phosphorylation, was blocked by p27, suggesting that cell cycle progression triggers checkpoint activation, likely as a consequence of replication stress. These data reveal that Ras is capable of inducing a DNA damage response with characteristics similar to those reported in precancerous lesions. Our findings also suggest that the frequent mutational activation of Ras in thyroid tumors reflects the ability of Ras-expressing cells to bypass checkpoints and evade apoptosis rather than to simply increase proliferative potential.

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Section: Ras-induced Apoptosis Ismentioning

confidence: 99%

Ras Triggers Ataxia-telangiectasia-mutated and Rad-3-related Activation and Apoptosis through Sustained Mitogenic Signaling

Fikaris

Lewis²,

Abulaiti

et al. 2006

Journal of Biological Chemistry

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“…Levels and cleavage products of various cyclins have been implicated in apoptosis induction (Finkielstein et al, 2002;Mazumder et al, 2002). Also, accumulation of CDKI P27 Kip1 and cyclin E in mice deficient in its E3 ligase Skp2 results in increased spontaneous apoptosis (Nakayama et al, 2000), and the level of Skp2 in gastric carcinomas modulates the phenotype of the cancer, presumably by affecting P27 expression (Masuda et al, 2002).…”

Section: Cell Deathmentioning

confidence: 99%

“…Overexpression of cyclin D1 has been reported to radiosensitize cancer cells, a finding that was ascribed to effects on the G2/M transition (Coco Martin et al, 1999). Caspase cleavage of both cyclin D1-CDK4 and cyclin A-CDK2 has been suggested to promote apoptosis in embryos following ionizing radiation exposure (Finkielstein et al, 2002), indicating that cell cycle arrest may be linked to apoptosis. Links between cyclin D and transcription have also been suggested (Coqueret, 2002).…”

Section: Cell Cyclementioning

confidence: 99%

The role of the ubiquitin/proteasome system in cellular responses to radiation

et al. 2003

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“…Cdk4 has not been described as a caspase 3 substrate, and we were unable to identify any potential cleavage sites. On the other hand, cyclin D1 from Xenopus laevis is cleaved by caspase 3 at a DEVD 278 site (18). However, we found that human cyclin D1 (which has the sequence EEVD) was not a substrate for caspase 3 under conditions in which known substrates were efficiently cleaved (data not shown).…”

Section: The C Terminus Of Rb Is Required For the Phosphorylation Of mentioning

confidence: 43%

Docking-Dependent Regulation of the Rb Tumor Suppressor Protein by Cdk4

Wallace

Ball

2004

Molecular and Cellular Biology

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Phosphorylation of target proteins by cyclin D1-Cdk4 requires both substrate docking and kinase activity. In addition to the ability of cyclin D1-Cdk4 to catalyze the phosphorylation of consensus sites within the primary amino acid sequence of a substrate, maximum catalytic activity requires the enzyme complex to anchor at a site remote from the phospho-acceptor site. A novel Cdk4 docking motif has been defined within a stretch of 19 amino acids from the C-terminal domain of the Rb protein that are essential for Cdk4 binding. Mutation or deletion of the docking motif prevents Cdk4-dependent phosphorylation of full-length Rb protein or C-terminal Rb fragments in vitro and in cells, while a peptide encompassing the Cdk4 docking motif specifically inhibits Cdk4-dependent phosphorylation of Rb. Cyclin D1-Cdk4 can overcome the growth-suppressive activity of Rb in both cell cycle progression and colony formation assays; however, while mutants of Rb in which the Cdk4 docking site has been either deleted or mutated retain growth suppressor activity, they are resistant to inactivation by cyclin D1-Cdk4. Finally, binding of Cdk4 to its docking site can inhibit cleavage of exogenous and endogenous Rb in response to distinct apoptotic signals. The Cdk4 docking motif in Rb gives insight into the mechanism by which enzyme specificity is ensured and highlights a role for Cdk4 docking in maintaining the Rb protein in a form that favors cell survival rather than apoptosis.The mechanisms employed by the protein kinase family of enzymes to ensure substrate and phospho-acceptor site specificity are beginning to receive increased interest as it becomes apparent that, in general, the information contained within the consensus phosphorylation motif is not sufficient to explain the fidelity of a given kinase in vivo. The broad consensus motif at the phosphorylation site targeted by the cyclin-cyclin-dependent kinases (cyclin-CDKs) is T/SPXR/K (23, 52); however, in order to gain specificity, these enzymes participate in a direct interaction with their substrate at a site distinct from the phospho-acceptor site (1, 2, 35, 48). In addition, at least some cyclin-CDKs are able to phosphorylate a given substrate through an interaction with an associated binding protein. For example, E2F1 can function as a targeting factor for cyclin A-Cdk2-dependent phosphorylation of its heterodimeric partner DP1 (14,30,58). Thus, the cyclin-CDKs belong to a growing class of kinases that require a specific docking interaction for efficient site-specific phosphorylation of a substrate (5).To date, the G 1 -associated kinase cyclin D-Cdk4 has been shown to phosphorylate only a limited subset of possible CDK target proteins (20, 28), suggesting that it has a strict requirement for determinants outside the phosphorylation motif and that these determinants are distinct from those required by other family members. There is good evidence that as well as providing increased specificity, cyclin D-Cdk4 substrate docking is required for the enzyme's maximal catalytic ...

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A Role for G1/S Cyclin-dependent Protein Kinases in the Apoptotic Response to Ionizing Radiation

Cited by 27 publications

References 58 publications

Ras Triggers Ataxia-telangiectasia-mutated and Rad-3-related Activation and Apoptosis through Sustained Mitogenic Signaling

Ras Triggers Ataxia-telangiectasia-mutated and Rad-3-related Activation and Apoptosis through Sustained Mitogenic Signaling

The role of the ubiquitin/proteasome system in cellular responses to radiation

Docking-Dependent Regulation of the Rb Tumor Suppressor Protein by Cdk4

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