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Al-Shami, A, Jhaver, KG, Vogel, P, Wilkins, C, Humphries, J, Davis, JJ, Xu, N, Potter, DG, Gerhardt, B, Mullinax, R, Shirley, CR, Anderson, SJ and Oravecz, T (2010) Regulators of the proteasome pathway, Uch37 and Rpn13, play distinct roles in mouse development. PLoS ONE 5:e13654
Rpn13 is a novel mammalian proteasomal receptor that has recently been identified as an amplification target in ovarian cancer. It can interact with ubiquitin and activate the deubiquitinating enzyme Uch37 at the 26S proteasome. Since neither Rpn13 nor Uch37 is an integral proteasomal subunit, we explored whether either protein is essential for mammalian development and survival. Deletion of Uch37 resulted in prenatal lethality in mice associated with severe defect in embryonic brain development. In contrast, the majority of Rpn13-deficient mice survived to adulthood, although they were smaller at birth and fewer in number than wild-type littermates. Absence of Rpn13 produced tissue-specific effects on proteasomal function: increased proteasome activity in adrenal gland and lymphoid organs, and decreased activity in testes and brain. Adult Rpn13(-/-) mice reached normal body weight but had increased body fat content and were infertile due to defective gametogenesis. Additionally, Rpn13(-/-) mice showed increased T-cell numbers, resembling growth hormone-mediated effects. Indeed, serum growth hormone and follicular stimulating hormone levels were significantly increased in Rpn13(-/-) mice, while growth hormone receptor expression was reduced in the testes. In conclusion, this is the first report characterizing the physiological roles of Uch37 and Rpn13 in murine development and implicating a non-ATPase proteasomal protein, Rpn13, in the process of gametogenesis.
Animals; Base Sequence; Blotting, Western; DNA Primers; Flow Cytometry; Membrane Glycoproteins/physiology; Mice; Mice, Mutant Strains; Nuclear Magnetic Resonance, Biomolecular; Oogenesis/physiology; Proteasome Endopeptidase Complex/metabolism; RNA, Messenger/genetics; Spermatogenesis/physiology