Evidence map›Paper›PMID 25088203›Full record

ArticleOncogene2015

BMI1 attenuates etoposide-induced G2/M checkpoints via reducing ATM activation.

F Wei, D Ojo, X Lin, N Wong, L He, J Yan, S Xu, P Major, D Tang

Open access · bronzeAbstract read
PubMed Publisher
In one paragraph

Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed, 1 pooled it
2.0field-weighted citation impact, top 14% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

17 citing papers in PubMed, 1 synthesis or guideline pooled it, 32 citations in OpenAlex.

  1. Pooled it
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  17. BMI1, ATM and DDR.Oncoscience · 2015
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 2 institutions in 1 country.

F Wei1] Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada [2] Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada [3] The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada [4] The Genetics Laboratory, Institute of Women and Children's Health, Longgang District, Shenzhen, Guangdong, P.R. China.
D Ojo1] Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada [2] Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada [3] The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada.
X Lin1] Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada [2] Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada [3] The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada.
N Wong1] Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada [2] Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada [3] The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada.
L He1] Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada [2] Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada [3] The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada [4] Massachusetts General Hospital (MGH), Harvard Medical School, Boston, MA, USA.
J Yan1] Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada [2] Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada [3] The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada.
S Xu1] Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada [2] Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada [3] The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada.
P MajorDepartment of Oncology, McMaster University, Hamilton, Ontario, Canada.
D Tang1] Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada [2] Father Sean O'Sullivan Research Institute, Hamilton, Ontario, Canada [3] The Hamilton Center for Kidney Research, St. Joseph's Hospital, Hamilton, Ontario, Canada.
McMaster University · CASt. Joseph’s Healthcare Hamilton · CA

Funding

Canadian Institutes of Health Research MOP-84381
6 · The paper itself

Abstract

The BMI1 protein contributes to stem cell pluripotency and oncogenesis via multiple functions, including its newly identified role in DNA damage response (DDR). Although evidence clearly demonstrates that BMI1 facilitates the repair of double-stranded breaks via homologous recombination (HR), it remains unclear how BMI1 regulates checkpoint activation during DDR. We report here that BMI1 has a role in G2/M checkpoint activation in response to etoposide (ETOP) treatment. Ectopic expression of BMI1 in MCF7 breast cancer and DU145 prostate cancer cells significantly reduced ETOP-induced G2/M arrest. Conversely, knockdown of BMI1 in both lines enhanced the arrest. Consistent with ETOP-induced activation of the G2/M checkpoints via the ATM pathway, overexpression and knockdown of BMI1, respectively, reduced and enhanced ETOP-induced phosphorylation of ATM at serine 1981 (ATM pS1981). Furthermore, the phosphorylation of ATM targets, including γH2AX, threonine 68 (T68) on CHK2 (CHK2 pT68) and serine 15 (S15) on p53 were decreased in overexpression and increased in knockdown BMI1 cells in response to ETOP. In line with the requirement of NBS1 in ATM activation, we were able to show that BMI1 associates with NBS1 and that this interaction altered the binding of NBS1 with ATM. BMI1 consists of a ring finger (RF), helix-turn-helix-turn-helix-turn (HT), proline/serine (PS) domain and two nuclear localization signals (NLS). Although deletion of either RF or HT did not affect the association of BMI1 with NBS1, the individual deletions of PS and one NLS (KRMK) robustly reduced the interaction. Stable expression of these BMI1 mutants decreased ETOP-induced ATM pS1981 and CHK2 pT68, but not ETOP-elicited γH2AX in MCF7 cells. Furthermore, ectopic expression of BMI1 in non-transformed breast epithelial MCF10A cells also compromised ETOP-initiated ATM pS1981 and γH2AX. Taken together, we provide compelling evidence that BMI1 decreases ETOP-induced G2/M checkpoint activation via reducing NBS1-mediated ATM activation.

Indexed as

Antineoplastic Agents, PhytogenicAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsCell Line, TumorDNA DamageEtoposideG2 Phase Cell Cycle CheckpointsGene Knockdown TechniquesHumansMCF-7 CellsMitogen-Activated Protein Kinase 7Nuclear ProteinsPhosphorylationAntineoplastic Agents, PhytogenicAtaxia Telangiectasia Mutated ProteinsATM protein, humanCell Cycle ProteinsEtoposideMAPK7 protein, humanMitogen-Activated Protein Kinase 7NBN protein, humanNuclear Proteins

Identifiers

PMID25088203
OpenAlexW2081921650

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.