Deregulation of Cdk2 causes Bim-mediated apoptosis in p53-deficient tumors following actin damage

Chae, Hee Don; Kim, B M; Yun, Un Jung; Shin, Deug Y.

doi:10.1038/onc.2008.46

Cited by 20 publications

(16 citation statements)

References 21 publications

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“…p21 has been reported to influence cell survival by acting both up- or down-stream of the intrinsic mitochondrial-mediated cell death pathway. p21 inhibits activation of CDK2/4/6 [51], kinases that induce translocation of Bax and Bim to the mitochondria [52, 53] and initiate mitochondrial membrane damage-induced cell death [54]. Pharmacological inhibition of CDK4/6 was recently shown to antagonize the cytotoxic effect of doxorubicin in several non-cardiac cells [55, 56].…”

Section: Discussionmentioning

confidence: 99%

Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21Cip1

Cheng

DiMichele

Rojas

et al. 2014

Journal of Molecular and Cellular Cardiology

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Clinical application of potent anthracycline anticancer drugs, especially doxorubicin (DOX), is limited by a toxic cardiac side effect that is not fully understood and preventive strategies are yet to be established. Studies in genetically modified mice have demonstrated that focal adhesion kinase (FAK) plays a key role in regulating adaptive responses of the adult myocardium to pathological stimuli through activation of intracellular signaling cascades that facilitate cardiomyocyte growth and survival. The objective of this study was to determine if targeted myocardial FAK activation could protect the heart from DOX-induced de-compensation and to characterize the underlying mechanisms. To this end, mice with myocyte-restricted FAK knock-out (MFKO) or myocyte-specific expression of an active FAK variant (termed SuperFAK) were subjected to DOX treatment. FAK depletion enhanced susceptibility to DOX-induced myocyte apoptosis and cardiac dysfunction, while elevated FAK activity provided remarkable cardioprotection. Our mechanistic studies reveal a heretofore unappreciated role for the protective cyclin-dependent kinase inhibitor p21 in the repression of the pro-apoptotic BH3-only protein Bim and the maintenance of mitochondrial integrity and myocyte survival. DOX treatment induced proteasomal degradation of p21, which exacerbated mitochondrial dysfunction and cardiomyocyte apoptosis. FAK was both necessary and sufficient for maintaining p21 levels following DOX treatment and depletion of p21 compromised FAK-dependent protection from DOX. These findings identify p21 as a key determinant of DOX resistance downstream of FAK in cardiomyocytes and indicate that cardiac-restricted enhancement of the FAK/p21 signaling axis might be an effective strategy to preserve myocardial function in patients receiving anthracycline chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21Cip1

Cheng

DiMichele

Rojas

et al. 2014

Journal of Molecular and Cellular Cardiology

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“…It was proposed, for instance, that starvation-induced apoptosis of endothelial cells is mediated through increased CDK2 activation (32). Very recently, deregulated CDK2 activation was also linked to increased Bim expression and apoptosis in response to actin damage (10). Furthermore, elevated activity of CDK2 has been found in certain forms of apoptosis, while overexpression of CDK2 accelerates thymocyte cell death (21).…”

Section: Discussionmentioning

confidence: 99%

Unscheduled Akt-Triggered Activation of Cyclin-Dependent Kinase 2 as a Key Effector Mechanism of Apoptin's Anticancer Toxicity

Maddika

Panigrahi

Wiecheć

et al. 2009

Molecular and Cellular Biology

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Apoptin, a protein from the chicken anemia virus, has attracted attention because it specifically kills tumor cells while leaving normal cells unharmed. The reason for this tumor selectivity is unclear and depends on subcellular localization, as apoptin resides in the cytoplasm of normal cells but in the nuclei of transformed cells. It was shown that nuclear localization and tumor-specific killing crucially require apoptin's phosphorylation by an as yet unknown kinase. Here we elucidate the pathway of apoptin-induced apoptosis and show that it essentially depends on abnormal phosphatidylinositol 3-kinase (PI3-kinase)/Akt activation, resulting in the activation of the cyclin-dependent kinase CDK2. Inhibitors as well as dominant-negative mutants of PI3-kinase and Akt not only inhibited CDK2 activation but also protected cells from apoptin-induced cell death. Akt activated CDK2 by direct phosphorylation as well as by the phosphorylation-induced degradation of the inhibitor p27 Kip1 . Importantly, we also identified CDK2 as the principal kinase that phosphorylates apoptin and is crucially required for apoptin-induced cell death. Immortalized CDK2-deficient fibroblasts and CDK2 knockdown cells were markedly protected against apoptin. Thus, our results not only decipher the pathway of apoptin-induced cell death but also provide mechanistic insights for the selective killing of tumor cells.

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“…Cell viability was assessed using a tetrazolium salt (WST-8)-based colorimetric assay from the Cell Counting Kit 8 (Dojindo, Kumamoto, Japan) (18) or by a trypan blue and propidium iodide exclusion assay (19). Statistical Analysis-The data were represented as mean Ϯ S.E.…”

Section: Methodsmentioning

confidence: 99%

Identification of a Novel Anti-apoptotic E3 Ubiquitin Ligase That Ubiquitinates Antagonists of Inhibitor of Apoptosis Proteins SMAC, HtrA2, and ARTS

Kim

et al. 2013

Journal of Biological Chemistry

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Background:Mitochondrial proapoptotic proteins such as SMAC, HtrA2, and ARTS promote apoptosis by antagonizing the inhibitor of apoptosis proteins (IAPs). Results: A novel anti-apoptotic E3 ubiquitin ligase, AREL1 was cloned and identified to interact with and ubiquitinate the IAP antagonists. Conclusion: AREL1 inhibits apoptosis through ubiquitinating the cytosolic IAP antagonists. Significance: AREL1-mediated degradation of IAP antagonists represents a new anti-apoptotic signaling pathway.

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Deregulation of Cdk2 causes Bim-mediated apoptosis in p53-deficient tumors following actin damage

Cited by 20 publications

References 21 publications

Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21Cip1

Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21Cip1

Unscheduled Akt-Triggered Activation of Cyclin-Dependent Kinase 2 as a Key Effector Mechanism of Apoptin's Anticancer Toxicity

Identification of a Novel Anti-apoptotic E3 Ubiquitin Ligase That Ubiquitinates Antagonists of Inhibitor of Apoptosis Proteins SMAC, HtrA2, and ARTS

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