| 1. |
- Cepeda, D., et al.
(författare)
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CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
- 2013
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 5:7, s. 999-1018
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Tidskriftsartikel (refereegranskat)abstract
- SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer. FBXO28 is identified as part of a SCF complex acting as a regulator of tumor cell proliferation and an important modifier of MYC function. FBXO28 may be a new prognostic factor in breast cancer and a new potential drug target in MYC- driven tumors.
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| 2. |
- Zegers, Catharina M L, et al.
(författare)
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Hypoxia imaging with [(18)F]HX4 PET in NSCLC patients : Defining optimal imaging parameters.
- 2013
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 109:1, s. 58-64
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: [(18)F]HX4 is a promising hypoxia PET-tracer. Uptake, spatio-temporal stability and optimal acquisition parameters for [(18)F]HX4 PET imaging were evaluated in non-small cell lung cancer (NSCLC) patients.MATERIALS AND METHODS: [(18)F]HX4 PET/CT images of 15 NSCLC patients were acquired 2h and 4h after injection (p.i.). Maximum standardized-uptake-value (SUVmax), tumor-to-blood-ratio (TBRmax), hypoxic fraction (HF) and contrast-to-noise-ratio (CNR) were determined for all lesions. To evaluate spatio-temporal stability, DICE-similarity and Pearson correlation coefficients were calculated. Optimal acquisition-duration was assessed by comparing 30, 20, 10 and 5min acquisitions.RESULTS: Considerable uptake (TBR >1.4) was observed in 18/25 target lesions. TBRmax increased significantly from 2h (1.6±0.3) to 4h p.i. (2.0±0.6). Uptake patterns at 2h and 4h p.i. showed a strong correlation (R=0.77±0.10) with a DICE similarity coefficient of 0.69±0.08 for the 30% highest uptake volume. Reducing acquisition-time resulted in significant changes in SUVmax and CNR. TBRmax and HF were only affected for scan-times of 5min.CONCLUSIONS: The majority of NSCLC lesions showed considerable [(18)F]HX4 uptake. The heterogeneous uptake pattern was stable between 2h and 4h p.i. [(18)F]HX4 PET imaging at 4h p.i. is superior to 2h p.i. to reach highest contrast. Acquisition time may be reduced to 10min without significant effects on TBRmax and HF.
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