Cyclin E in normal physiology and disease states

Chu, Chengcai; Geng, Yan; Zhou, Yu; Siciński, Piotr

doi:10.1016/j.tcb.2021.05.001

Cited by 84 publications

(47 citation statements)

References 102 publications

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“…Cyclin E/CDK2 complex then phosphorylates numerous substrates to control essential cellular processes, such as progression through the restriction point (R point), initiation of DNA replication, and regulation of histone biosynthesis among others. By the end of S phase, Cyclin E protein levels are completely degraded by the SCF FBW7 ubiquitin ligase complex, thus eliminating Cyclin E/CDK2 activity up to the subsequent G1 phase ( Hwang and Clurman, 2005 ; Chu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

Fagundes

Teixeira

2021

Front. Cell Dev. Biol.

122

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DNA replication must be precisely controlled in order to maintain genome stability. Transition through cell cycle phases is regulated by a family of Cyclin-Dependent Kinases (CDKs) in association with respective cyclin regulatory subunits. In normal cell cycles, E-type cyclins (Cyclin E1 and Cyclin E2, CCNE1 and CCNE2 genes) associate with CDK2 to promote G1/S transition. Cyclin E/CDK2 complex mostly controls cell cycle progression and DNA replication through phosphorylation of specific substrates. Oncogenic activation of Cyclin E/CDK2 complex impairs normal DNA replication, causing replication stress and DNA damage. As a consequence, Cyclin E/CDK2-induced replication stress leads to genomic instability and contributes to human carcinogenesis. In this review, we focus on the main functions of Cyclin E/CDK2 complex in normal DNA replication and the molecular mechanisms by which oncogenic activation of Cyclin E/CDK2 causes replication stress and genomic instability in human cancer.

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Section: Introductionmentioning

confidence: 99%

Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

Fagundes

Teixeira

2021

Front. Cell Dev. Biol.

122

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“…We speculate that other G1 regulators may be downregulated in SSA-treated cells, leading to the SSA-induced G1 phase arrest. Numerous factors in addition to p27, cyclin E1, and E2F1 are involved in regulating the G1/S phase transition [3,9,24]. E2F1 activates the gene expression of numerous factors that drive the initiation of the S phase [7].…”

Section: Discussionmentioning

confidence: 99%

“…Among these regulators, cyclin family proteins and cyclin-dependent kinases (CDKs) promote cell cycle progression [1,2]. In G1/S phase transition, cyclin E1 and cyclin E2 (collectively known as cyclin E), along with Cdk2, are the key players that phosphorylate a variety of substrates [3][4][5][6]. Rb is a substrate of the cyclin E-Cdk2 complex; it binds the E2F1 transcription factor and represses the transcriptional activity of E2F1 [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…After phosphorylation by cyclin E-Cdk2, Rb releases E2F1, and E2F1, in turn, activates the transcription of numerous genes that drive the initiation of the S phase. The genes encoding cyclin E are controlled by E2F1, and thus the cyclin E-Cdk2 complex and E2F1 form a positive feedback loop that promotes G1/S phase transition [3,4,6,9]. The cyclin E-Cdk2 complex also phosphorylates Smad3, CBP/p300, and NPAT, leading to cell cycle progression [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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CCNE1 and E2F1 Partially Suppress G1 Phase Arrest Caused by Spliceostatin A Treatment

Kikuchi

Kaida

2021

IJMS

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The potent splicing inhibitor spliceostatin A (SSA) inhibits cell cycle progression at the G1 and G2/M phases. We previously reported that upregulation of the p27 cyclin-dependent kinase inhibitor encoded by CDKN1B and its C-terminal truncated form, namely p27*, which is translated from CDKN1B pre-mRNA, is one of the causes of G1 phase arrest caused by SSA treatment. However, the detailed molecular mechanism underlying G1 phase arrest caused by SSA treatment remains to be elucidated. In this study, we found that SSA treatment caused the downregulation of cell cycle regulators, including CCNE1, CCNE2, and E2F1, at both the mRNA and protein levels. We also found that transcription elongation of the genes was deficient in SSA-treated cells. The overexpression of CCNE1 and E2F1 in combination with CDKN1B knockout partially suppressed G1 phase arrest caused by SSA treatment. These results suggest that the downregulation of CCNE1 and E2F1 contribute to the G1 phase arrest induced by SSA treatment, although they do not exclude the involvement of other factors in SSA-induced G1 phase arrest.

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“…A previous report indicates that overexpression of a fusion protein of truncated cyclin E and Cdk2 leads to M-phase entry in differentiated primary neurons ( Walton et al, 2019 ), although cell cycle reentry may result in neuronal cell death ( Barrio-Alonso et al, 2018 ). However, Cdk2 was barely expressed at 2 months old ( Figure 1D ), suggesting that cyclin E has a Cdk-independent function ( Chu et al, 2021 ). Consistent with this, it has been reported that cyclin E is involved in synaptic plasticity through the negative regulation and sequestration of Cdk5, suggesting that cyclin E functions without activation of CDKs ( Odajima et al, 2011 ).…”

Section: Cell Cycle Regulators In Post-mitotic Neuronmentioning

confidence: 99%

Alternative Functions of Cell Cycle-Related and DNA Repair Proteins in Post-mitotic Neurons

Akagawa

Nabeshima

Kawauchi

2021

Front. Cell Dev. Biol.

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Proper regulation of neuronal morphological changes is essential for neuronal migration, maturation, synapse formation, and high-order function. Many cytoplasmic proteins involved in the regulation of neuronal microtubules and the actin cytoskeleton have been identified. In addition, some nuclear proteins have alternative functions in neurons. While cell cycle-related proteins basically control the progression of the cell cycle in the nucleus, some of them have an extra-cell cycle-regulatory function (EXCERF), such as regulating cytoskeletal organization, after exit from the cell cycle. Our expression analyses showed that not only cell cycle regulators, including cyclin A1, cyclin D2, Cdk4/6, p21cip1, p27kip1, Ink4 family, and RAD21, but also DNA repair proteins, including BRCA2, p53, ATM, ATR, RAD17, MRE11, RAD9, and Hus1, were expressed after neurogenesis, suggesting that these proteins have alternative functions in post-mitotic neurons. In this perspective paper, we discuss the alternative functions of the nuclear proteins in neuronal development, focusing on possible cytoplasmic roles.

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Cyclin E in normal physiology and disease states

Cited by 84 publications

References 102 publications

Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

CCNE1 and E2F1 Partially Suppress G1 Phase Arrest Caused by Spliceostatin A Treatment

Alternative Functions of Cell Cycle-Related and DNA Repair Proteins in Post-mitotic Neurons

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