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

Abstract

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...

cAMP-mediated Induction of Cyclin E Sensitizes Growth-arrested Adipose Stem Cells to DNA Damage–induced Apoptosis

“…This sensitization by cAMP was dependent on cyclin E expression, thus we concluded that cyclin E induction seems to play an important role in ␥-irradiation-induced apoptosis of ASCs. The proapoptotic effect of cyclin E was apparently independent of cdk2 activity, which is in accordance with other reports (Leonce et al, 2001;Mazumder et al, 2007). Cyclin E expression has been shown to decline late in the apoptotic process, due to caspase-dependent proteolysis of cyclin E (Mazumder et al, 2002).…”

Mitomycin C and doxorubicin elicit conflicting signals by causing accumulation of cyclin E prior to p21WAF1/CIP1 elevation in human hepatocellular carcinoma cells

“…Although we showed that anticancer drug-induced accumulation of cyclin E was clearly associated with the G 1 -S-phase transition, we could not exclude the possibility that cyclin E accumulation was also linked to apoptosis. Indeed, genotoxic stress induces both cyclin E and an associated CDK2 activity (40), and cyclin E induction is linked to apoptosis (41). However, the fact that sublethal concentrations of mitomycin C and doxorubicin also caused accumulation of cyclin E eliminated the possibility of an association between such accumulation and apoptosis.…”

Targeting prostate cancer based on signal transduction and cell cycle pathways

“…189,204 Current models of the molecular network coordinating responses to DNA damage place p53 at the crossroads of several stress response pathways critical for maintaining genome integrity; including cell cycle arrest, DNA repair, mitotic catastrophe, apoptosis and cellular senescence. [205][206][207][208][209][210][211] The mechanisms by which p53 directs cells down each of these alternative avenues of cell fate determination differs among cells of various All of these pathways interact to regulate the induction of cell cycle progression and apoptosis. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways normally serve to suppress apoptosis while p53, which is induced by certain chemotherapeutic drugs and ionizing radiation, will result in increases in pro-apoptotic family members and in some cases, growth factors which may activate certain growth factor receptors.…”