Interaction of a Cyclin E Fragment with Ku70 Regulates Bax-Mediated Apoptosis

Mazumder, Suparna; Plesca, Dragos; Kinter, Michael; Almasan, Alexandru

doi:10.1128/mcb.01448-06

Cited by 63 publications

(60 citation statements)

References 47 publications

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“…60 Interestingly, Bax can be liberated from Ku70 by a caspase-generated cyclin E fragment resulting in an amplification of the apoptosis signal. 61 Together, these data suggest an anti-apoptotic role of this DNA repair enzyme that can be controlled in a p53-dependent manner.…”

Section: P53-binding Proteinsmentioning

confidence: 86%

The dark side of a tumor suppressor: anti-apoptotic p53

2008

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Depending on multiple factors DNA damage leads either to cell cycle arrest or apoptosis. One of the main players deciding the fate of a cell is the tumor suppressor p53 that modulates these responses in a transcription-dependent and -independent manner. Over the past few years, however, strong evidence accumulated that p53 engages also powerful pro-survival pathways by transcriptionally activating a multitude of genes whose products efficiently counteract apoptosis. Our review summarizes the current knowledge concerning approximately forty p53-regulated proteins that exert their anti-apoptotic potential by interfering with diverse cellular processes. These activities are surely essential for normal development and maintenance of a healthy organism, but may easily turn into the dark side of the tumor suppressor p53 contributing to tumorigenesis.

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Section: P53-binding Proteinsmentioning

confidence: 86%

The dark side of a tumor suppressor: anti-apoptotic p53

2008

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“…Moreover, once cyclin E is cleaved, the resulting p18-cyclin E derivative functions quite differently. In fact, yeast two-hybrid analyses designed to identify p18-cyclin E-binding partners could not find most of the common partners of cyclin E. 44 So not only does it look different, but p18-cyclin E also acts differently from cyclin E, being a killer and no longer a healer, therefore a story reminiscent of Dr. Jekyll and Mr. Hyde. Cyclin E and its derivatives in cancer.…”

Section: Discussionmentioning

confidence: 99%

A Jekyll and Hyde Role of Cyclin E in the Genotoxic Stress Response: Switching from Cell Cycle Control to Apoptosis Regulation

Mazumder¹,

Plesca²

2007

Cell Cycle

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Cyclin E protein levels and associated kinase activity rise in late G 1 phase, reach a peak at the G 1 /S transition, and quickly decline during S phase. The cyclin E/Cdk2 complex has a well-established function in regulating two fundamental biological processes: cell cycle progression and DNA replication. However, cyclin E expression is deregulated in a wide range of tumors. Our recent reports have uncovered a critical role for cyclin E, independent of Cdk2, in the cell death of hematopoietic tumor cells exposed to genotoxic stress. An 18-kD C-terminal fragment of cyclin E, p18-cyclin E, which is generated by caspase-mediated cleavage in hematopoietic cells during genotoxic stressinduced apoptosis has a critical role in the amplification of the intrinsic apoptotic pathway. By interacting with Ku70, p18-cyclin E liberates Bax, which participates in the amplification of apoptosis by sustaining a positive feedback loop targeting mitochondria. This process is independent of p53 function and new RNA or protein synthesis. Therefore, cyclin E emerges as an arbiter of the genotoxic stress response by regulating a finite physiological balance between cell proliferation and death in hematopoietic cells.Keywords cyclin E; Cdk2; Ku70; Bax; caspase; apoptosis; cell cycle; genotoxic stress CDK2 Dependent Roles of Cyclin ECyclins regulate cell cycle progression by binding to their catalytic interacting partners, cyclin dependent kinases (Cdks). The activity of Cdk's is positively controlled by cyclins and negatively by binding to Cdk inhibitors (CKIs). 1,2 The transit between the G 1 and S phases of the cell cycle is primarily regulated by the cyclin E/Cdk2 complex. 3,4 Even though D-type cyclins are also involved in the G 1 /S transition, all phenotypic and developmental defects in mice caused by cyclin D1 deficiency can be rescued by cyclin E knock-in at the cyclin D1 locus, indicating that the function of cyclin D1 may be replaced by cyclin E. 5 Cyclin E1, referred to here as cyclin E, is the best known E-type cyclin and has 395 amino acids and a molecular weight of 50 kDa. 6,7 In normal cells, many gene products required for S-phase progression are under the control of the E2F family of transcription factors, which become free upon phosphorylation of the retinoblastoma protein (Rb) by cyclin E/Cdk2. Constitutive or ectopic expression of cyclin E can accelerate G 1 progression 4 and chromosome instability, 8,9 presumably because of inappropriate S-phase entry/progression. 10 The cyclin E/Cdk2 complex plays an important role in the initiation of DNA replication. 4,11 In Xenopus, there is strong evidence implicating cyclin E/Cdk2 in the initiation of DNA replication and in centrosome duplication. 12 A recent report in mammals indicates that cyclin E also plays a kinase-independent function in DNA replication by facilitating minichromosome maintenance (MCM) loading through physical interaction with CDT1 and MCM. 13The expression of cyclin E oscillates during cell cycle progression due to tight regulation at transcript...

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“…Ku70 is known to suppress apoptosis by negatively regulating Bax activation (43)(44)(45)(46)(47)(48). Upon apoptotic stimulation, acetylation of Ku70 in the C-terminal flexible linker region results in activating Bax, thereby promoting apoptosis (43)(44)(45)48).…”

Section: Discussionmentioning

confidence: 99%

“…Next, apoptosis can be initiated by activation of the proapoptotic factor Bax (54,55), and Ku70 suppresses Bax-mediated apoptosis by sequestering Bax away from mitochondria through the Ku70-Bax interaction (43)(44)(45)(46)(47)(48). Cotransfection of Bax with control vector, c-Src, or v-Src, a highly activated variant of c-Src, showed that the levels of Bax-mediated apoptosis were decreased by expression of c-Src and v-Src (Fig.…”

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confidence: 99%

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Src Acts as an Effector for Ku70-dependent Suppression of Apoptosis through Phosphorylation of Ku70 at Tyr-530

Morii

Kubota

Honda

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangSrc-family tyrosine kinases are widely expressed in many cell types and participate in a variety of signal transduction pathways. Despite the significance of Src in suppression of apoptosis, its mechanism remains poorly understood. Here we show that Src acts as an effector for Ku70-dependent suppression of apoptosis. Inhibition of endogenous Src activity promotes UV-induced apoptosis, which is impaired by Ku70 knockdown. Src phosphorylates Ku70 at Tyr-530, being close to the possible acetylation sites involved in promotion of apoptosis. Src-mediated phosphorylation of Ku70 at Tyr-530 decreases acetylation of Ku70, whereas Src inhibition augments acetylation of Ku70. Importantly, knockdown-rescue experiments with stable Ku70 knockdown cells show that the nonphosphorylatable Y530F mutant of Ku70 reduces the ability of Ku70 to suppress apoptosis accompanied by augmentation of Ku70 acetylation. Our results reveal that Src plays a protective role against hyperactive apoptotic cell death by reducing apoptotic susceptibility through phosphorylation of Ku70 at Tyr-530.

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Interaction of a Cyclin E Fragment with Ku70 Regulates Bax-Mediated Apoptosis

Cited by 63 publications

References 47 publications

The dark side of a tumor suppressor: anti-apoptotic p53

The dark side of a tumor suppressor: anti-apoptotic p53

A Jekyll and Hyde Role of Cyclin E in the Genotoxic Stress Response: Switching from Cell Cycle Control to Apoptosis Regulation

Src Acts as an Effector for Ku70-dependent Suppression of Apoptosis through Phosphorylation of Ku70 at Tyr-530

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