Abstract
TRIM71 (tripartite motif-containing 71) belongs to the TRIM-NHL protein family, which plays a conserved role in regulating early development and differentiation. However, the molecular functions of TRIM71 have remained largely unknown. Here, we explored the role of TRIM71 together with modulation of Lin28B-let-7-HMGA2 (high-mobility group AT-hook 2) signaling in tumorigenesis. TRIM71 overexpression opposed Lin28B-induced transformation in primary cells and inhibited tumor formation in a mouse model. Specific knockdown of TRIM71 expression increased cancer cell proliferation and invasion. Conversely, overexpression of wild-type TRIM71 in non-small cell lung carcinoma (NSCLC) cells in which Lin28B-let-7-HMGA2 signaling was conserved decreased both cancer cell phenotypes. More importantly, overexpression of an ubiquitin transfer activity-deficient TRIM71 mutant in NSCLC cells had no effect on proliferation or invasion, regardless of the conservation status of Lin28B-let-7-HMGA2 signaling. The tumorigenic inhibitory action of TRIM71 was antagonized by overexpression of the TRIM71 downstream targets, Lin28B and HMGA2. Furthermore, a bioinformatics analysis revealed that TRIM71 expression was downregulated in various types of cancer tissue from patients. Taken together, these data indicate that TRIM71 acts through post-transcriptional repression of Lin28B and subsequent modulation of let-7-HMGA2 signaling during tumorigenesis to potentially function as a tumor suppressor.
Highlights
TRIM71, a member of the tripartite motif (TRIM)-NHL family consisting of TRIM2, -3, -32, and -71, was initially discovered as a temporal cell fate regulator in Caenorhabditis elegans early development and has since been shown to be relatively conserved in metazoans
This region is critically important in discriminating between Lin28B and its paralog Lin28A [6, 13, 19]. Both Lin28B and Lin28A interact with the loop sequence of pre-let-7, an interaction that modulates oligouridylation and degradation of pre-let-7; the maturation process leads to the well-known post-transcriptional tumor suppressor, let-7 [7]
An essential downstream target of let-7 is HMGA2 mRNA, which contains eight let-7 target sites within its 3'-untranslated region (3'-UTR) [9, 10]. This post-transcriptional modulation of Lin28B-let-7HMGA2 signaling motivated us to investigate whether TRIM71 has a potential role in this signaling during tumorigenesis
Summary
TRIM71 (tripartite motif-containing 71), a member of the TRIM-NHL family consisting of TRIM2, -3, -32, and -71, was initially discovered as a temporal cell fate regulator in Caenorhabditis elegans early development and has since been shown to be relatively conserved in metazoans. It is known as lin-41 (lineage variant 41), which is a genetic suppressor of a let-7 loss-of-function mutant [1, 2]. TRIM71 shares structural similarities in the N-terminal tripartite motif (TRIM), composed of a RING domain, B-box and coiled-coil regions, with other TRIMdomain–containing protein family members. With the exception of this RING domain, the physiological functions of other structurally defined motifs in TRIM71 remain unknown
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