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In a separate study, Tg expression of β-TrCP1 or β-TrCPΔF (a dominant-negative mutant with the F-box deleted) in intestine, liver, and kidney induces intestinal adenomas as well as hepatic and urothelial tumors, likely through nuclear accumulation of β-catenin.
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Orange box, region deleted in tyr a. Black arrowheads, primer sites for identification of SNPs.
We further generated a SOCS6 mutant, from which the SOCS box was deleted (SOCS6-ΔSB), and showed that SOCS6-ΔSB failed to target to mitochondria or induce mitochondrial fragmentation.
There is a small decrease in the ability of Aven to do so if the RGG box is deleted but it is only significant at the highest UV dose and is a modest effect, perhaps 2-fold.
To determine whether an intact SOCS box is required for targeting SOCS6 to mitochondria, we next generated a SOCS6 mutant in which the terminal helix 3 motif (amino acids 523 535) of the SOCS box was deleted, and showed that this mutant lost mitochondrial localization as well as the ability to induce mitochondrial fragmentation.
Importantly, in recent studies (31), the effects of Tcf7l2 inactivation in the adult mouse β cell (using an alternative model in which exon 10, encoding the DNA-binding HMG box, was deleted) were not examined beyond 12 weeks of age, such that any effects later in life would have been missed.
Curiously, avian USP4 presents notable deviations from the signatures of this paralog: of the six bird genomes surveyed, all bear mutations in crucial residues for the ubiquitin-exchange mechanism [ 32], i.e. Arg40 and/or Met24 mutated in all, disruption of DUSP-UBL linker residues (a.a. 88 92) in chicken, QQD box region deleted in duck, and so on.
