Abstract
RNF12/RLIM is a RING domain-containing E3 ubiquitin ligase whose function has only begun to be elucidated recently. Although RLIM was reported to play important roles in some biological processes such as imprinted X-chromosome inactivation and regulation of TGF-β pathway etc., other functions of RLIM are largely unknown. Here, we identified RLIM as a novel E3 ubiquitin ligase for c-Myc, one of the most frequently deregulated oncoproteins in human cancers. RLIM associates with c-Myc in vivo and in vitro independently of the E3 ligase activity of RLIM. Moreover, RLIM promotes the polyubiquitination of c-Myc protein independently of Ser62 and Thr58 phosphorylation of c-Myc. However, RLIM-mediated ubiquitination does not affect c-Myc stability. Instead, RLIM inhibits the transcriptional activity of c-Myc through which RLIM restrains cell proliferation. Our results suggest that RLIM may function as a tumor suppressor by controlling the activity of c-Myc oncoprotein.
Highlights
RLIM is a RING domain-containing E3 ubiquitin ligase first reported to play an important role in the chicken limb development by controlling CLIM abundance [1]
We revealed a novel function of RLIM as an E3 ubiquitin ligase for c-Myc
We found RLIM interacts with c-Myc in cells by reciprocal immunoprecipitation
Summary
RLIM is a RING domain-containing E3 ubiquitin ligase first reported to play an important role in the chicken limb development by controlling CLIM abundance [1]. In Xenopus, Rlim maintains proper stoichiometry of Xlim-1/Ldb and confers proper function of the Spemann organizer [2]. It modulates telomere length homeostasis through proteolysis of TRF1 [3]. RLIM was identified as a component of the TGF-β superfamily signaling pathways [5, 6] It controls embryonic stem cell fate and morphogenesis in Zebrafish embryos by targeting the negative regulator Smad for proteasomal degradation [6]. The most exciting finding was that RLIM initiates imprinted X-chromosome inactivation (iXCI) by targeting REX1 for degradation [8, 9] It is dispensable for random form of XCI (rXCI) in mouse embryonic
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