التفاصيل البيبلوغرافية
| العنوان: |
RGS2 Protein Degradation is Mediated by a Novel Cullin 4B/F‐box 44 E3 Ligase Complex |
| المؤلفون: |
Sjogren, Benita, Storaska, Andrew, Swaney, Steven, Neubig, Richard |
| المصدر: |
The FASEB Journal ; volume 29, issue S1 ; ISSN 0892-6638 1530-6860 |
| بيانات النشر: |
Wiley |
| سنة النشر: |
2015 |
| المجموعة: |
Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: |
Hypertension and heart failure are major health issues and there is a need to identify more effective treatments. R egulator of G protein S ignaling 2 (RGS2) is highly expressed in both heart and vascular smooth muscle and regulates Gα q signaling. RGS2 ‐/‐ mice are hypertensive, show enhanced responses to vasoconstrictors and lower tolerability to pressure overload. Over ‐expression of RGS2 reduces cardiac hypertrophy and we have shown that pharmacologically enhanced RGS2 protein expression has functional effects on G protein signaling. Therefore, we hypothesize that enhancing RGS2 protein expression is a novel route in treating cardiovascular disease. RGS2 is rapidly degraded through the proteasome, but the specific enzymes involved are not known. Thus, the goal of the current study was to identify the molecular machinery responsible for RGS2 protein degradation. A siRNA screen to identify genes that regulate RGS2 protein levels identified components of a putative cullin‐RING E3 ligase (CRL). siRNA knock‐down of F‐box 44 (FBXO44) or cullin 4B (CUL4B), but not CUL4A or CUL1, led to a significant increase in RGS2 protein levels and stability. Overexpression of FBXO44 and CUL4B decreased RGS2 protein levels. FBXO44 associates with both RGS2, CUL4B and the adaptor protein DDB‐1 in cells resulting in a novel E3 ligase protein complex able to degrade RGS2. Studies are now underway to characterize the molecular mechanisms of the FBXO44‐RGS2 interaction. RGS proteins are difficult drug targets due to their mode of action being through protein‐protein interactions. Inhibiting a more druggable protein within the degradation pathway could be a way to increase RGS2 protein levels and function. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1096/fasebj.29.1_supplement.618.15 |
| الاتاحة: |
http://dx.doi.org/10.1096/fasebj.29.1_supplement.618.15 |
| Rights: |
http://onlinelibrary.wiley.com/termsAndConditions#vor |
| رقم الانضمام: |
edsbas.C99B1A54 |
| قاعدة البيانات: |
BASE |