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

Fagundes, Rafaela; Teixeira, Leonardo K.

doi:10.3389/fcell.2021.774845

Cited by 119 publications

(54 citation statements)

References 122 publications

(167 reference statements)

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“…7A). As it has been demonstrated that CDK2 activation requires the formation of the cyclin E/CDK2 complex (46), we speculated that the starvationinduced cyclin E down-regulation may decrease the formation of the cyclin E/CDK2 complex, leading to the inhibition of CDK2 activity. Consistent with this hypothesis, we found that the CDK2 inhibitor roscovitine notably reduced the levels of p-SIRT2 S331 , Ac-ATG4B K39 , SQSTM1, and Ac--tubulin K40 but elevated the protein level of LC3-II (Fig.…”

Section: Starvation Activates Sirt2 By Suppressing Cyclin E/cdk2mentioning

confidence: 98%

Deacetylation of ATG4B promotes autophagy initiation under starvation

et al. 2022

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Eukaryotes initiate autophagy when facing environmental changes such as a lack of external nutrients. However, the mechanisms of autophagy initiation are still not fully elucidated. Here, we showed that deacetylation of ATG4B plays a key role in starvation-induced autophagy initiation. Specifically, we demonstrated that ATG4B is activated during starvation through deacetylation at K39 by the deacetylase SIRT2. Moreover, starvation triggers SIRT2 dephosphorylation and activation in a cyclin E/CDK2 suppression–dependent manner. Meanwhile, starvation down-regulates p300, leading to a decrease in ATG4B acetylation at K39. K39 deacetylation also enhances the interaction of ATG4B with pro-LC3, which promotes LC3-II formation. Furthermore, an in vivo experiment using Sirt2 knockout mice also confirmed that SIRT2-mediated ATG4B deacetylation at K39 promotes starvation-induced autophagy initiation. In summary, this study reveals an acetylation-dependent regulatory mechanism that controls the role of ATG4B in autophagy initiation in response to nutritional deficiency.

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Section: Starvation Activates Sirt2 By Suppressing Cyclin E/cdk2mentioning

confidence: 98%

Deacetylation of ATG4B promotes autophagy initiation under starvation

et al. 2022

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“…As a substrate of FBXW7, cyclin E, a nuclear protein that interacts with and activates cyclin-dependent kinase 2 (CDK2) to phosphorylate proteins, facilitates G 1 /S phase transition and is degraded at the boundary of the S/G 2 phase, whereas the overexpression of cyclin E has been detected in human cancer cells associated with cell cycle deregulation and chromosome instability (CIN) ( 161 , 162 ). FBXW7 mutations lead to the aberrant accumulation of its substrate cyclin E in CRC samples, conferring abnormality of chromosome congression during metaphase as well as ensuing chromosome transmission, implicating the role of FBXW7/cyclin E axis in regulating CIN ( 163 ).…”

Section: Fbxw7 and The Hallmarks Of Cancermentioning

confidence: 99%

FBXW7 and the Hallmarks of Cancer: Underlying Mechanisms and Prospective Strategies

et al. 2022

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FBXW7, a member of the F-box protein family within the ubiquitin–proteasome system, performs an indispensable role in orchestrating cellular processes through ubiquitination and degradation of its substrates, such as c-MYC, mTOR, MCL-1, Notch, and cyclin E. Mainly functioning as a tumor suppressor, inactivation of FBXW7 induces the aberrations of its downstream pathway, resulting in the occurrence of diseases especially tumorigenesis. Here, we decipher the relationship between FBXW7 and the hallmarks of cancer and discuss the underlying mechanisms. Considering the interplay of cancer hallmarks, we propose several prospective strategies for circumventing the deficits of therapeutic resistance and complete cure of cancer patients.

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“…This protein complex regulates cell-cycle progression and DNA replication through the phosphorylation of specific substrates. In oncogenic conditions, the Cyclin E/CDK2 complex affects normal DNA replication, causing DNA replication stress, leading to cellular instability—a precursor of cancer development [ 55 ].…”

Section: Resultsmentioning

confidence: 99%

Molecular Insights in Uterine Leiomyosarcoma: A Systematic Review

Sparić

Andjić²,

Babovic³

et al. 2022

IJMS

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Uterine fibroids (UFs) are the most common benign tumors of female genital diseases, unlike uterine leiomyosarcoma (LMS), a rare and aggressive uterine cancer. This narrative review aims to discuss the biology and diagnosis of LMS and, at the same time, their differential diagnosis, in order to distinguish the biological and molecular origins. The authors performed a Medline and PubMed search for the years 1990–2022 using a combination of keywords on the topics to highlight the many genes and proteins involved in the pathogenesis of LMS. The mutation of these genes, in addition to the altered expression and functions of their enzymes, are potentially biomarkers of uterine LMS. Thus, the use of this molecular and protein information could favor differential diagnosis and personalized therapy based on the molecular characteristics of LMS tissue, leading to timely diagnoses and potential better outcomes for patients.

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

Cited by 119 publications

References 122 publications

Deacetylation of ATG4B promotes autophagy initiation under starvation

Deacetylation of ATG4B promotes autophagy initiation under starvation

FBXW7 and the Hallmarks of Cancer: Underlying Mechanisms and Prospective Strategies

Molecular Insights in Uterine Leiomyosarcoma: A Systematic Review

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