| PAC1 gene knockout reveals an essential role of chaperone-mediated 20S proteasome biogenesis and latent 20S proteasomes in cellular homeostasis. | |
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MedLine Citation:
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PMID: 20498273 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The 26S proteasome, a central enzyme for ubiquitin-dependent proteolysis, is a highly complex structure comprising 33 distinct subunits. Recent studies have revealed multiple dedicated chaperones involved in proteasome assembly both in yeast and in mammals. However, none of these chaperones is essential for yeast viability. PAC1 is a mammalian proteasome assembly chaperone that plays a role in the initial assembly of the 20S proteasome, the catalytic core of the 26S proteasome, but does not cause a complete loss of the 20S proteasome when knocked down. Thus, both chaperone-dependent and -independent assembly pathways exist in cells, but the contribution of the chaperone-dependent pathway remains unclear. To elucidate its biological significance in mammals, we generated PAC1 conditional knockout mice. PAC1-null mice exhibited early embryonic lethality, demonstrating that PAC1 is essential for mammalian development, especially for explosive cell proliferation. In quiescent adult hepatocytes, PAC1 is responsible for producing the majority of the 20S proteasome. PAC1-deficient hepatocytes contained normal amounts of the 26S proteasome, but they completely lost the free latent 20S proteasome. They also accumulated ubiquitinated proteins and exhibited premature senescence. Our results demonstrate the importance of the PAC1-dependent assembly pathway and of the latent 20S proteasomes for maintaining cellular integrity. |
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Authors:
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Katsuhiro Sasaki; Jun Hamazaki; Masato Koike; Yuko Hirano; Masaaki Komatsu; Yasuo Uchiyama; Keiji Tanaka; Shigeo Murata |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-24 |
Journal Detail:
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Title: Molecular and cellular biology Volume: 30 ISSN: 1098-5549 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-07-12 Completed Date: 2010-08-06 Revised Date: 2011-07-22 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: United States |
Other Details:
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Languages: eng Pagination: 3864-74 Citation Subset: IM |
Affiliation:
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Laboratory of Frontier Science, Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Setagayaku, Tokyo, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Catalytic Domain / genetics Gene Knockout Techniques Homeostasis / genetics Mammals / genetics, metabolism Mice Mice, Knockout Mice, Transgenic Molecular Chaperones / chemistry, genetics, metabolism* Physiological Processes / genetics Proteasome Endopeptidase Complex / chemistry, genetics, metabolism* Saccharomyces cerevisiae / genetics, metabolism Ubiquitinated Proteins |
| Chemical | |
Reg. No./Substance:
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0/Molecular Chaperones; 0/Ubiquitinated Proteins; EC 3.4.25.1/Proteasome Endopeptidase Complex; EC 3.4.99.-/ATP dependent 26S protease |
| Comments/Corrections | |
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