Cdt1 Is Differentially Targeted for Degradation by Anticancer Chemotherapeutic Drugs

Σταθοπούλου, Αθανασία; Roukos, Vassilis; Petropoulou, Chariklia; Kotsantis, Panagiotis; Karantzelis, Nikolaos; Nishitani, Hideo; Lygerou, Zoi; Taraviras, Stavros

doi:10.1371/journal.pone.0034621

Cited by 28 publications

(21 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Indeed, it has been shown already that accumulated CDT1, because of reduced degradation results in DNA rereplication and cell apoptosis [39]. It has been also shown that CDT1 destruction occurs in cells after treatment with chemotherapeutics [46] and after UV irradiation [47, 48]. We report here that in cancer cells, but not in non-transformed cells, this mechanism was consistently impaired by CDT2 depletion.…”

Section: Discussionsupporting

confidence: 61%

The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase

et al. 2014

View full text Add to dashboard Cite

CDT2/L2DTL/RAMP is one of the substrate receptors of the Cullin Ring Ubiquitin Ligase 4 that targets for ubiquitin mediated degradation a number of substrates, such as CDT1, p21 and CHK1, involved in the regulation of cell cycle and survival. Here we show that CDT2 depletion was alone able to induce the apoptotic death in 12/12 human cancer cell lines from different tissues, regardless of the mutation profile and CDT2 expression level. Cell death was associated to rereplication and to loss of CDT1 degradation. Conversely, CDT2 depletion did not affect non-transformed human cells, such as immortalized kidney, lung and breast cell lines, and primary cultures of endothelial cells and osteoblasts. The ectopic over-expression of an activated oncogene, such as the mutation-activated RAS or the amplified MET in non-transformed immortalized breast cell lines and primary human osteoblasts, respectively, made cells transformed in vitro, tumorigenic in vivo, and susceptible to CDT2 loss. The widespread effect of CDT2 depletion in different cancer cells suggests that CDT2 is not in a synthetic lethal interaction to a single specific pathway. CDT2 likely is a non-oncogene to which transformed cells become addicted because of their enhanced cellular stress, such as replicative stress and DNA damage.

show abstract

Section: Discussionsupporting

confidence: 61%

The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase

et al. 2014

View full text Add to dashboard Cite

show abstract

“…DNA damage was induced by treating cells with etoposide, a topoisomerase inhibitor producing DNA strand breaks (32), to enhance degradation of Mdm2 (Fig. S4A).…”

Section: Resultsmentioning

confidence: 99%

REGγ deficiency promotes premature aging via the casein kinase 1 pathway

Zhao

Wei

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Our recent studies suggest a role for the proteasome activator REG (11S regulatory particles, 28-kDa proteasome activator)γ in the regulation of tumor protein 53 (p53). However, the molecular details and in vivo biological significance of REGγ-p53 interplay remain elusive. Here, we demonstrate that REGγ-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1δ and p53. Antibody array analysis led us to identify CK1δ as a direct target of REGγ. Silencing CK1δ or inhibition of CK1δ activity prevented decay of murine double minute (Mdm)2. Interestingly, a massive increase of p53 in REGγ −/− tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced. Allelic p53 haplodeficiency in REGγ-deficient mice attenuated premature aging features. Furthermore, introducing exogenous Mdm2 to REGγ −/− MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REGγ-CK1-Mdm2-p53 regulatory pathway. Given the conflicting evidence regarding the "antiaging" and "proaging" effects of p53, our results indicate a key role for CK1δ-Mdm2-p53 regulation in the cellular aging process. These findings reveal a unique model that mimics acquired aging in mammals and indicates that modulating the activity of the REGγ-proteasome may be an approach for intervention in aging-associated disorders.casein kinase 1 | PA28γ P remature aging refers to unusual acceleration of the natural aging process and is induced by multiple factors such as genetics, environment, and stress conditions. Many biological markers of premature aging have been described over the past century, including blindness, gray/yellow hair, ear atrophy, osteoporosis, lordokyphosis of the spine, reduced hair regrowth, delayed wound healing, and a shortened lifespan (1, 2). Recently, progress has been made in understanding some of the mechanisms of premature aging (3, 4). DNA damage, oxidative stress, and mitochondrial DNA (mtDNA) mutations are associated with premature aging and may be contributing agents. Furthermore, abnormalities in several cancer-related proteins such as cyclin-dependent kinase inhibitor 1 (p21), tumor protein 53 (p53), and E2F family of transcription factors (retinoblastoma-associated protein; E2F1) also are known to cause premature aging phenotypes (5-8). Given that longer lifespan is mostly associated with an increased cancer incidence, maintaining the balance between longevity and reduced risk of cancer remains a formidable task.Discrepancies between proaging and antiaging effects of p53 were observed in different experimental systems. A p53 hypermorphic mouse model that harbored a mutant p53 allele (m-p53) displayed resistance to spontaneous cancers, a shortened lifespan, and premature aging phenotypes (2). The role of p53 in promoting aging is supported by a different mouse model, in which a 44-kDa truncated naturally occurring isoform of p53 (p44 +/+ ) is expressed (7). The p44 +/+ mice displayed enhanced p53 activity and phenot...

show abstract

“…[22][23][24] When cells are exposed to irradiation or other DNA-damaging reagents, Cdt1 is degraded via the same PCNA-and CRL4 Cdt2 -dependent pathways. [25][26][27][28][29][30] Exposure of cells to UV (UV) irradiation induces helix-distorting DNA lesions, such as cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine-pyrimidone photoproducts. Upon UV irradiation, Cdt1 is rapidly degraded within minutes, primarily dependent on the nucleotide excision repair (NER) process, 31,32 based on the finding that Cdt1 degradation is attenuated when xeroderma pigmentosum (XP)-related proteins are inactivated or depleted.…”

Section: Q-x-x-[i/l/m/v]-t-d-[f/y]-[f/y]-x-x-[k/r]-[k/r] (Pip Boxmentioning

confidence: 99%

Mismatch repair proteins recruited to ultraviolet light-damaged sites lead to degradation of licensing factor Cdt1 in the G1 phase

et al. 2017

Self Cite

View full text Add to dashboard Cite

Cdt1 is rapidly degraded by CRL4Cdt2 E3 ubiquitin ligase after UV (UV) irradiation. Previous reports revealed that the nucleotide excision repair (NER) pathway is responsible for the rapid Cdt1-proteolysis. Here, we show that mismatch repair (MMR) proteins are also involved in the degradation of Cdt1 after UV irradiation in the G1 phase. First, compared with the rapid (within »15 min) degradation of Cdt1 in normal fibroblasts, Cdt1 remained stable for »30 min in NER-deficient XP-A cells, but was degraded within »60 min. The delayed degradation was also dependent on PCNA and CRL4 Cdt2. The MMR proteins Msh2 and Msh6 were recruited to the UV-damaged sites of XP-A cells in the G1 phase. Depletion of these factors with small interfering RNAs prevented Cdt1 degradation in XP-A cells. Similar to the findings in XP-A cells, depletion of XPA delayed Cdt1 degradation in normal fibroblasts and U2OS cells, and co-depletion of Msh6 further prevented Cdt1 degradation. Furthermore, depletion of Msh6 alone delayed Cdt1 degradation in both cell types. When Cdt1 degradation was attenuated by high Cdt1 expression, repair synthesis at the damaged sites was inhibited. Our findings demonstrate that UV irradiation induces multiple repair pathways that activate CRL4Cdt2 to degrade its target proteins in the G1 phase of the cell cycle, leading to efficient repair of DNA damage.

show abstract

Cdt1 Is Differentially Targeted for Degradation by Anticancer Chemotherapeutic Drugs

Cited by 28 publications

References 50 publications

The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase

The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase

REGγ deficiency promotes premature aging via the casein kinase 1 pathway

Mismatch repair proteins recruited to ultraviolet light-damaged sites lead to degradation of licensing factor Cdt1 in the G1 phase

Contact Info

Product

Resources

About