Cyclin D1 promotes BRCA2-Rad51 interaction by restricting cyclin A/B-dependent BRCA2 phosphorylation

Chalermrujinanant, Chonvara; Michowski, Wojciech; Sittithumcharee, Gunya; Esashi, Fumiko; Jirawatnotai, Siwanon

doi:10.1038/onc.2015.354

Cited by 20 publications

(19 citation statements)

References 50 publications

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“…Cyclin D1 facilitates RAD51 recruitment to DNA repair foci (27). Therefore, we reasoned that cyclin D1-depletion may similarly sensitize cells to WEE1 inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…Several reports have indicated that cell cycle regulator proteins directly control proteins in DNA repair pathways (27, 37). Given that cyclin D1 facilities RAD51 recruitment to DNA repair foci and is a downstream target of mTOR signaling, we asked whether depletion of cyclin D1 expression was sufficient to override AZD2014-mediated potentiation to AZD1775 (27, 38).…”

Section: Discussionmentioning

confidence: 99%

“…Given that cyclin D1 facilities RAD51 recruitment to DNA repair foci and is a downstream target of mTOR signaling, we asked whether depletion of cyclin D1 expression was sufficient to override AZD2014-mediated potentiation to AZD1775 (27, 38). We showed that AZD1775 treatment was insufficient to induce HR repair in CRISPR CCND1 -deficient cells compared to sgLacZ-control cells.…”

Section: Discussionmentioning

confidence: 99%

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Synergy of WEE1 and mTOR Inhibition in Mutant KRAS-Driven Lung Cancers

Hai

Liu

Bufe

et al. 2017

Clinical Cancer Research

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Purpose KRAS-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multi-targeted therapy may offer a plausible strategy to effectively treat KRAS-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring KRAS mutations. Experimental Design We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human KRAS-mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines. Murine autochthonous and human transplant models were used to test the therapeutic efficacy and pharmacodynamic effects of dual treatment. Results We demonstrate that combined inhibition of mTOR and WEE1 induced potent synergistic cytotoxic effects selectively in KRAS-mutant NSCLC cell lines, delayed human tumor xenograft growth and caused tumor regression in a murine lung adenocarcinoma model. Mechanistically, we show that inhibition of mTOR potentiates WEE1 inhibition by abrogating compensatory activation of DNA repair, exacerbating DNA damage in KRAS-mutant NSCLC, and that this effect is due in part to reduction in cyclin D1. Conclusions These findings demonstrate that compromised DNA repair underlies the observed potent synergy of WEE1 and mTOR inhibition and support clinical evaluation of this dual therapy for patients with KRAS-mutant lung cancers.

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“…Cyclin D1 facilitates RAD51 recruitment to DNA repair foci (27). Therefore, we reasoned that cyclin D1-depletion may similarly sensitize cells to WEE1 inhibition.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Synergy of WEE1 and mTOR Inhibition in Mutant KRAS-Driven Lung Cancers

Hai

Liu

Bufe

et al. 2017

Clinical Cancer Research

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“…The Ku protein heterodimer Ku70/80, which is critical for the repair of dsDNA breaks [36] , was initially induced in response to DNA damage and was decreased after prolonged treatment by each agent, thus supporting the effect of the chemicals on the induction of the DNA damage response. In addition, JA and JB inhibited DNA repair, including the suppression of RPA proteins, which are involved in binding to single-stranded DNA to protect DNA lesions during DNA replication, recombination and repair [36,37] , and the suppression of mismatch repair proteins [38] and recombinase RAD51, which are important in mediating homologous recombination [39] . We also noted that the inhibitory effect of JB on repair proteins was less than that of JA, in agreement with the observations that JB induced delayed apoptosis and lower cytotoxic activity.…”

Section: Discussionmentioning

confidence: 99%

Jungermannenone A and B induce ROS- and cell cycle-dependent apoptosis in prostate cancer cells in vitro

et al. 2016

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Aim: Jungermannenone A and B (JA, JB) are new ent-kaurane diterpenoids isolated from Chinese liverwort Jungermannia fauriana, which show anti-proliferation activities in cancer cells. In this study we investigated the mechanisms underlying the anticancer action of JA and JB in PC3 human prostate cancer cells in vitro. Methods: A panel of 9 human cancer cell lines was tested. Cell proliferation was assessed with a real-time cell analyzer and MTT assay. Cell apoptosis, cell cycle distribution and ROS levels were measured using cytometry. Mitochondrial damage was examined by transmission electron microscopy. DNA damage was detected with comet assay. Apoptotic, DNA damage-and cell cycle-related proteins were analyzed using Western blotting. The expression of DNA repair genes was measured with qRT-PCR. Results: Both JA and JB exerted potent anti-proliferative action against the 9 cancer cell lines, and PC3 cells were more sensitive with IC 50 values of 1.34±0.09 and 4.93±0.20 μmol/L, respectively. JA (1.5 μmol/L) and JB (5 μmol/L) induced PC3 cell apoptosis, which was attenuated by the caspase inhibitor Z-VAD. Furthermore, both JA and JB caused mitochondrial damage and ROS accumulation in PC3 cells, whereas vitamin C blocked the ROS accumulation and attenuated the cytotoxicity of JA and JB. Moreover, both JA and JB induced DNA damage, accompanied by downregulated DNA repair proteins Ku70/Ku80 and RDA51. JA induced marked cell cycle arrest at the G 0 /G 1 phase, which was related to c-Myc suppression, whereas JB enforced the cell cycle blockade in the G 2 /M phase, which associated with activation of the JNK signaling. Conclusion: Both JA and JB induce prostate cancer apoptosis via ROS accumulation and induction of cell cycle arrest.

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“…This property is restricted to the isoform a of the protein. Cyclin D1 is also part of the RAD51/BRCA2 (breast cancer 2) complexes at DNA damage sites and has been shown to facilitate HR (homologous recombination)-mediated DNA repair in a CDK4-independent fashion in several types of tumors [8,92]. Cyclin D1 seems to play a dual role, sustaining the activation of DNA-PK and ATM whilst interacting with the DNA repair machinery.…”

Section: Nuclear Cyclin D1 Controls the Dna Damage Response And Genommentioning

confidence: 99%

The double dealing of cyclin D1

2019

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Abbreviations: aa, amino acid ; AR, androgen receptor; ATM, ataxia telangectasia mutant;ATR, ATM and Rad3-related; CDK, cyclin-dependent kinase; ChREBP, carbohydrate response element binding protein; CIP, CDK-interacting protein; CHK1/2, checkpoint kinase 1/2; CKI, CDK inhibitor; DDR, DNA damage response; DMP1, cyclin D-binding myb-like protein; DSB, double-strand DNA break; DNA-PK, DNA-dependent protein kinase; ER, estrogen receptor; FASN, fatty acid synthase; GSK3β, glycogen synthase-3β; HAT, histone acetyltransferase; HDAC, histone deacetylase; HK2, hexokinase 2; HNF4α, and hepatocyte nuclear factor 4α; HR, homologous recombination; IR, ionizing radiation; KIP, kinase inhibitory protein; MCL, mantle cell lymphoma; NHEJ, non-homologous end-joining; PCAF, p300/CREB binding-associated protein; PGC1α, PPARγ co-activator 1α; PEST, proline-glutamic acid-serine-threonine, PK, pyruvate kinase; PPAR, peroxisome proliferator-activated receptor; RB1, retinoblastoma protein; ROS, reactive oxygen species; SRC, steroid receptor coactivator; STAT, signal transducer and activator of transcription; TGFβ, transforming growth factor β; UPS, ubiquitinproteasome system; USP22, ubiquitin-specific peptidase 22; XPO1 (or CRM1) exportin 1. AbstractThe cell cycle is tightly regulated by cyclins and their catalytic moieties, the cyclindependent kinases (CDKs). Cyclin D1, in association with CDK4/6, acts as a mitogenic sensor and integrates extracellular mitogenic signals and cell cycle progression. When deregulated (overexpressed, accumulated, inappropriately located), cyclin D1 becomes an oncogene and is recognized as a driver of solid tumors and hemopathies. Recent studies on the oncogenic roles of cyclin D1 reported non-canonical functions dependent on the partners of cyclin D1 and its location within tumor cells or tissues. Support for these new functions was provided by various mouse models of oncogenesis. Finally, proteomic and transcriptomic data identified complex cyclin D1 networks. This review focuses on these aspects of cyclin D1 pathophysiology, which may be crucial for targeted therapy.

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Cyclin D1 promotes BRCA2-Rad51 interaction by restricting cyclin A/B-dependent BRCA2 phosphorylation

Cited by 20 publications

References 50 publications

Synergy of WEE1 and mTOR Inhibition in Mutant KRAS-Driven Lung Cancers

Synergy of WEE1 and mTOR Inhibition in Mutant KRAS-Driven Lung Cancers

Jungermannenone A and B induce ROS- and cell cycle-dependent apoptosis in prostate cancer cells in vitro

The double dealing of cyclin D1

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