Regulation of ubiquitin ligase dynamics by the nucleolus

Autor: Stephen Lee, Lakshman Gunaratnam, Amanda Carrigan, Mireille Khacho, Karim Mekhail, Robert R.J. Hache
Rok vydání: 2005
Předmět:
Nucleolus
Recombinant Fusion Proteins
Ubiquitin-Protein Ligases
Molecular Sequence Data
Protein Sorting Signals
urologic and male genital diseases
Article
Mice
03 medical and health sciences
0302 clinical medicine
Ubiquitin
Proto-Oncogene Proteins c-mdm2
Cell Line
Tumor
Proto-Oncogene Proteins
Animals
Humans
Amino Acid Sequence
neoplasms
Research Articles
030304 developmental biology
0303 health sciences
biology
Tumor Suppressor Proteins
Nuclear Proteins
Fluorescence recovery after photobleaching
Cell Biology
Hydrogen-Ion Concentration
Rats
Ubiquitin ligase
Cell biology
Transport protein
Protein Transport
Von Hippel-Lindau Tumor Suppressor Protein
030220 oncology & carcinogenesis
Ubiquitin ligase complex
biology.protein
Mdm2
Tumor Suppressor Protein p53
Cell Nucleolus
Fluorescence Recovery After Photobleaching
Zdroj: The Journal of Cell Biology
ISSN: 1540-8140
0021-9525
Popis: Cellular pathways relay information through dynamic protein interactions. We have assessed the kinetic properties of the murine double minute protein (MDM2) and von Hippel-Lindau (VHL) ubiquitin ligases in living cells under physiological conditions that alter the stability of their respective p53 and hypoxia-inducible factor substrates. Photobleaching experiments reveal that MDM2 and VHL are highly mobile proteins in settings where their substrates are efficiently degraded. The nucleolar architecture converts MDM2 and VHL to a static state in response to regulatory cues that are associated with substrate stability. After signal termination, the nucleolus is able to rapidly release these proteins from static detention, thereby restoring their high mobility profiles. A protein surface region of VHL's β-sheet domain was identified as a discrete [H+]-responsive nucleolar detention signal that targets the VHL/Cullin-2 ubiquitin ligase complex to nucleoli in response to physiological fluctuations in environmental pH. Data shown here provide the first evidence that cells have evolved a mechanism to regulate molecular networks by reversibly switching proteins between a mobile and static state.
Databáze: OpenAIRE
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