| 1. |
- Larsson, Lars, 1952-, et al.
(författare)
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Adaptation by alternative RNA splicing of slow troponin T isoforms in type 1 but not type 2 Charcot-Marie-Tooth disease
- 2008
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Ingår i: American Journal of Physiology - Cell Physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 295:3, s. 722-731
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Tidskriftsartikel (refereegranskat)abstract
- Slow troponin T (TnT) plays an indispensable role in skeletal muscle function. Alternative RNA splicing in the NH2-terminal region produces high-molecular-weight (HMW) and low-molecular-weight (LMW) isoforms of slow TnT. Normal adult slow muscle fibers express mainly HMW slow TnT. Charcot-Marie-Tooth disease (CMT) is a group of inherited peripheral polyneuropathies caused by various neuronal defects. We found in the present study that LMW slow TnT was significantly upregulated in demyelination form type 1 CMT (CMT1) but not axonal form type 2 CMT (CMT2) muscles. Contractility analysis showed an increased specific force in single fibers isolated from CMT1 but not CMT2 muscles compared with control muscles. However, an in vitro motility assay showed normal velocity of the myosin motor isolated from CMT1 and CMT2 muscle biopsies, consistent with their unchanged myosin isoform contents. Supporting a role of slow TnT isoform regulation in contractility change, LMW and HMW slow TnT isoforms showed differences in the molecular conformation in conserved central and COOH-terminal regions with changed binding affinity for troponin I and tropomyosin. In addition to providing a biochemical marker for the differential diagnosis of CMT, the upregulation of LMW slow TnT isoforms under the distinct pathophysiology of CMT1 demonstrates an adaptation of muscle function to neurological disorders by alternative splicing modification of myofilament proteins.
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| 2. |
- Sundqvist, Anders, et al.
(författare)
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Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7)
- 2005
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 1:6, s. 379-391
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Tidskriftsartikel (refereegranskat)abstract
- The sterol regulatory element binding protein (SREBP) family of transcription factors controls cholesterol and lipid metabolism. The nuclear forms of these proteins are rapidly degraded by the ubiquitin-proteasome pathway, but the signals and factors required for this are unknown. Here, we identify a phosphodegron in SREBP1a that serves as a recognition motif for the SCF(Fbw7) ubiquitin ligase. Fbw7 interacts with nuclear SREBP1a and enhances its ubiquitination and degradation in a manner dependent on the phosphorylation of T426 and S430 by GSK-3. Fbw7 also degrades nuclear SREBP1c and SREBP2, and inactivation of endogenous Fbw7 results in stabilization of nuclear SREBP1 and -2, enhanced expression of SREBP target genes, enhanced synthesis of cholesterol and fatty acids, and enhanced receptor-mediated uptake of LDL. Thus, our results suggest that Fbw7 may be a major regulator of lipid metabolism through control of the phosphorylation-dependent degradation of the SREBP family of transcription factors.
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| 3. |
- Zhang, Jin-Ting, et al.
(författare)
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Nuclear to cytoplasmic shift of p33ING1b protein from normal oral mucosa to oral squamous cell carcinoma in relation to clinicopathological variables
- 2008
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Ingår i: Journal of Cancer Research and Clinical Oncology. - : Springer Science and Business Media LLC. - 0171-5216 .- 1432-1335. ; 134:3, s. 421-426
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: p33ING1b, as a candidate tumour suppressor gene, has been found to be expressed a proportion of oral squamous cell carcinomas (OSCCs), however, its clinicopathological significance is not studied yet. Our aim was to investigate association of p33ING1b expression with clinicopathological variables and particularly interesting new cysteine-histidine rich protein (PINCH) in OSCCs. Methods: p33ING1b expression was immumohistochemically examined in 20 normal oral mucosa specimens and 49 OSCCs. Results: Normal squamous cells showed only p33ING1b nuclear expression (no cytoplasmic expression), with a rate of 90% positive cases. While 24% of OSCCs appeared cytoplasmic expression (11 of them with weak nuclear staining) and the rest tumours (76%) were negative for p33 ING1b. Furthermore, the cases having lymph node metastasis showed a higher frequency of positive cytoplasmic expression than those without metastasis (P = 0.03). The p33ING1b cytoplasmic expression was positively related to PINCH expression (P = 0.04), the cases positive for both proteins had a high rate of the metastasis (P = 0.03). Conclusions: The transfer of p33ING1b protein from the nucleus to the cytoplasm may result in loss of normal cellular function of the protein, which might play a role in the tumourigenesis and metastasis of OSCCs. © 2007 Springer-Verlag.
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