The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1

Proc. Natl. Acad. Sci. U.S.A.

Mei

et al. 2012

The biological function of Tripartite Motif 39 (TRIM39) remains largely unknown. In this study, we report that TRIM39 regulates the steady-state levels of p21 and is a pivotal determinant of cell fate. Ablation of TRIM39 leads to destabilization of p21 and increased G1/S transition in unperturbed cells. Furthermore, DNA damage-induced p21 accumulation is completely abolished in cells with depleted TRIM39. As a result, silencing of TRIM39 abrogates the G2 checkpoint induced by genotoxic stress, leading to increased mitotic entry and, ultimately, apoptosis. Importantly, we show p21 is a crucial downstream effector of TRIM39 mediating G1/S transition and DNA damage-induced G2 arrest. Mechanistically, TRIM39 interacts with p21, which subsequently prevents Cdt2 from binding to p21, therefore blocking ubiquitylation and proteasomal degradation of p21 mediated by CRL4 Cdt2 E3 ligase. Strikingly, we found a significant correlation between p21 abundance and TRIM39 expression levels in human hepatocellular carcinoma samples. Our findings identify a causal role for TRIM39 in regulating cell cycle progression and the balance between cytostasis and apoptosis after DNA damage via stabilizing p21.

supporting

confidence: 54%

“…Notably, MOAP-1 was recently reported as a substrate of the APC/C Cdh1 ubiquitin ligase. TRIM39 was proposed to regulate MOAP-1 via acting on APC/C Cdh1 (1). Unfortunately, the molecular mechanisms underlying TRIM39-dependent regulation of APC/C Cdh1 are obscure.…”

Section: Discussionmentioning

confidence: 99%

TRIM39 regulates cell cycle progression and DNA damage responses via stabilizing p21

Proc. Natl. Acad. Sci. U.S.A.

Mei

et al. 2012

“…3A). MST2, a core component of the Hippo signaling pathway, regulates cell proliferation, growth and apoptosis [14], and the E3 ubiquitinprotein ligase TRIM39 has a pro-apoptotic effect by inhibiting APC/CCdh1-mediated poly-ubiquitination [26]. Therefore, we mutated the miR-155-binding site resides in the 3′UTR of the MST2 and TRIM39 mRNAs and performed luciferase reporter assays using a miR-155 mimic and a miR-155 inhibitor (Fig.…”

Section: Mst2 Is a Direct Target Of Mir-155 In Vsmcsmentioning

confidence: 98%

miR-155-dependent regulation of mammalian sterile 20-like kinase 2 (MST2) coordinates inflammation, oxidative stress and proliferation in vascular smooth muscle cells

Yang

Zheng

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

et al. 2015

In response to vascular injury, inflammation, oxidative stress, and cell proliferation often occur simultaneously in vascular tissues. We previously observed that microRNA-155 (miR-155), which is implicated in proliferation and inflammation is involved in neointimal hyperplasia; however, the molecular mechanisms by which it regulates these processes remain largely unknown. In this study, we observed that vascular smooth muscle cell (VSMC) proliferation and neointimal formation in wire-injured femoral arteries were reduced by the loss of miR-155 and increased by the gain of miR-155. The proliferative effect of miR-155 was also observed in cultured VSMCs. Notably, expression of the miR-155-target protein mammalian sterile 20-like kinase 2 (MST2) was increased in the injured arteries of miR-155-/- mice. miR-155 directly repressed MST2 and thus activated the extracellular signal-regulated kinase (ERK) pathway by promoting an interaction between RAF proto-oncogene serine/threonine-protein kinase (Raf-1) and mitogen-activated protein kinase kinase (MEK) and stimulating inflammatory and oxidative stress responses; together, these effects lead to VSMC proliferation and vascular remodeling. Our data reveal that MST2 mediates miR-155-promoted inflammatory and oxidative stress responses by altering the interaction of MEK with Raf-1 and MST2 in response to vascular injury. Therefore, suppression of endogenous miR-155 might be a novel therapeutic strategy for vascular injury and remodeling.

“…Recently, we reported that involvement of the tripartite motif 39 (Trim39) E3 ubiquitin ligase in controlling DNA damageinduced apoptosis through inhibition of the anaphase promoting complex (APC/C), a multiprotein ubiquitin ligase that controls multiple cell cycle regulators, including cyclins, geminin, and others (5). Surprisingly, analysis of cell cycle progression in cells lacking Trim39 now suggests that it also might be important for G1/S progression/initiation of DNA replication in some cell types but that a target other than the APC/C was likely involved.…”

mentioning

confidence: 99%

Ubiquitylation of p53 by the APC/C inhibitor Trim39

Proc. Natl. Acad. Sci. U.S.A.

Huang

Chen

et al. 2012

Self Cite

Tripartite motif 39 (Trim39) is a RING domain-containing E3 ubiquitin ligase able to inhibit the anaphase-promoting complex (APC/C) directly. Through analysis of Trim39 function in p53-positive and p53-negative cells, we have found, surprisingly, that p53-positive cells lacking Trim39 could not traverse the G1/S transition. This effect did not result from disinhibition of the APC/C. Moreover, although Trim39 loss inhibited etoposide-induced apoptosis in p53-negative cells, apoptosis was enhanced by Trim39 knockdown in p53-positive cells. Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. Depletion of Trim39 significantly increased p53 protein levels and cell growth retardation in multiple cell lines. We found that the relative importance of Trim39 and the well-characterized p53-directed E3 ligase, murine double minute 2 (MDM2), varied between cell types. In cells that were relatively insensitive to the MDM2 inhibitor, nutlin-3a, apoptosis could be markedly enhanced by siRNA directed against Trim39. As such, Trim39 may serve as a potential therapeutic target in tumors with WT p53 when MDM2 inhibition is insufficient to elevate p53 levels and apoptosis.