LncRNA MT1DP Aggravates Cadmium-Induced Oxidative Stress by Repressing the Function of Nrf2 and is Dependent on Interaction with miR-365.
Ming GaoChangying LiMing XuYun LiuMin CongSijin LiuPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2018)
Although cadmium (Cd)-induced hepatoxicity is well established, pronounced knowledge gaps remain existed regarding the inherent cellular signaling that dictates Cd toxicity. Specifically, the molecular basis for determining the equilibrium between prosurvival and proapoptotic signaling remains poorly understood. Thus, it is recently revealed that long non-coding RNA (lncRNA) MT1DP, a pseudogene in the metallothionein (MT) family, promoted Cd-induced cell death through activating the RhoC-CCN1/2-AKT pathway and modulating MT1H induction. Here, first the dependency of MT1DP induction on MTF1, an important transcriptional factor in driving the mRNA expression of MT1 members is defined. Additionally, a bridge molecule between MT1DP and nuclear factor erythroid 2-related factor 2 (Nrf2) is established: miR-365. Mechanistically, MT1DP induction under Cd stress decreases the nuclear factor erythroid 2-related factor 2 (Nrf2) level to evoke oxidative stress through the elevation of miR-365, which acted to repress the Nrf2 level via direct binding to its 3'UTR. In contrast to the competing endogenous RNA (ceRNA) mechanism, a new mechanism is proposed: MT1DP elevated the miR-365 level though stabilizing its RNA via direct binding. Collectively, the combined data demonstrate a crucial role of MT1DP in reducing the Nrf2-mediated protection of cells, and this is dependent on the interplay with miR-365. Hence, the study further expands the knowledge of inducible endogenous lncRNA in modulating oxidative stress.
Keyphrases
- long non coding rna
- oxidative stress
- poor prognosis
- nuclear factor
- diabetic rats
- cell proliferation
- induced apoptosis
- long noncoding rna
- cell death
- signaling pathway
- toll like receptor
- healthcare
- gene expression
- ischemia reperfusion injury
- dna damage
- magnetic resonance imaging
- risk assessment
- heavy metals
- inflammatory response
- hydrogen peroxide
- cell cycle arrest
- transcription factor
- artificial intelligence
- nucleic acid
- nitric oxide
- immune response
- binding protein
- dna binding