Tumor-suppressor NFκB2 p100 interacts with ERK2 and stabilizes PTEN mRNA via inhibition of miR-494

Abstract

Emerging evidence from The Cancer Genome Atlas (TCGA) has revealed that nfκb2 gene encoding p100 is genetically deleted or mutated in human cancers, implicating NFκB2 as a potential tumor suppressor. However, the molecular mechanism underlying the anti-tumorigenic action of p100 remains poorly understood. Here, we report that p100 inhibits cancer cell anchorage-independent growth, a hallmark of cellular malignancy, by stabilizing the tumor suppressor PTEN mRNA via a mechanism that is independent of p100’s inhibitory role in NFκB activation. We further demonstrate that the regulatory effect of p100 on PTEN expression is mediated by its downregulation of miR-494 as a result of the inactivation of ERK2, in turn leading to inhibition of c-Jun/AP-1-dependent transcriptional activity. Furthermore, we identify that p100 specifically interacts with non-phosphorylated ERK2 and prevents ERK2 phosphorylation and nuclear translocation. Moreover, the death domain at C-terminal of p100 is identified as being crucial and sufficient for its interaction with ERK2. Taken together, our findings provide novel mechanistic insights into the understanding of the tumor suppressive role for NFκB2 p100.

Retracted: Effects of microRNA‐494 on proliferation, migration, invasion, and apoptosis of medulloblastoma cells by mediating c‐myc through the p38 MAPK signaling pathway

“…PTEN is a well-characterized tumor suppressor that contributes to the inactivation of the Akt signaling pathway and suppression of cell survival, cell proliferation, and oncogenic cellular transformation. 29 The p38 MAPK signaling pathway has been demonstrated to play a vital role in a number of physiological or pathological conditions, including cancer development. 30,31 A previously conducted study has reported that p38 promotes tumorigenesis by mediating tumor cell invasion and metastasis, and another study has shown that the p38 pathway functions as a tumor suppressor by inhibiting cell proliferation in lung cancer.…”

NFκB2 p52 stabilizes rhogdiβ mRNA by inhibiting AUF1 protein degradation via a miR‐145/Sp1/USP8‐dependent axis

“…The shRNA constructs specifically targeting mouse and human p52, AUF1, USP8, and Sp1 were purchased from Open Biosystems (Thermo Fisher Scientific, Pittsburgh, PA). Plasmids pBabe‐puro p100 (1‐900)/p52 (1‐442) were generously provided by Dr Han‐Fei Ding (Cancer Center, Georgia Regents University, Augusta, GA) and have been used in our published studies . Mouse Sp1 3′‐UTR luciferase reporter and Sp1 3′‐UTR point mutation luciferase reporters (with miR‐145, miR‐29c, and miR‐125b binding sites mutated) were cloned into pMIR report luciferase vector.…”

“…Plasmids pBabe-puro p100 (1-900)/p52 (1-442) were generously provided by Dr Han-Fei Ding (Cancer Center, Georgia Regents University, Augusta, GA) 27 and have been used in our published studies. 28 Mouse Sp1 3′-UTR luciferase reporter and Sp1 3′-UTR point mutation luciferase reporters (with miR-145, miR-29c, and miR-125b binding sites mutated) were cloned into pMIR report luciferase vector. Constructs expressing pFRT/TO/HIS/FLAG/HA-AUF1 29 and FLAG/HA-USP8 30 were obtained from Addgene (Cambridge, MA).…”

Inhibition of PHLPP2/cyclin D1 protein translation contributes to the tumor suppressive effect of NFκB2 (p100)

“…Plasmids pBabe-puro p100 (1-900)/p52 (1–442) were generously provided by Dr. Han-Fei Ding (Cancer Center, Georgia Regents University, Augusta, GA) [19] and has been used in our published studies [49]. Mouse cyclin d1 3′-UTR luciferase reporter and cyclin d1 3′-UTR point mutation luciferase reporter (miR-302d binding site was mutated) were cloned into the pMIR report luciferase vector.…”

“…The protein concentration was determined using Nano Drop 2000 (Thermo Scientific, Holtsville, NY, USA). The cell extract (60–80 μg/sample) was subjected to Western Blotting with specific antibodies as described in our previous studies [49]. The densitometry analyses of the protein bands were performed using the ImageQuant 5.2 software (GE Healthcare, Pittsburgh, PA).…”