Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mixed lineage kinase domain-like (MLKL) protein was recently found to play a critical role in necrotic cell death. To explore its role in neurological diseases, we measured MLKL protein expression after ischemia injury in a mouse model. We found that MLKL expression significantly increased 12 h after ischemia/reperfusion (I/R) injury with peak levels at 48 h. Inhibition of MLKL by intraperitoneal administration of NSA significantly reduced infarct volume and improved neurological deficits after 75 min of ischemia and 24 h of reperfusion. Further, we found NSA reduced MLKL levels via the ubiquitination proteasome pathway, but not by inhibiting RNA transcription. Interestingly, NSA administration increased cleaved PARP-1 levels, indicating the protective effects of MLKL inhibition is not related to apoptosis. These findings suggest MLKL is a new therapeutic target for neurological pathologies like stroke. Therefore, promoting degradation of MLKL may be a novel avenue to reduce necrotic cell death after ischemic brain injury.
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PMID:The degradation of mixed lineage kinase domain-like protein promotes neuroprotection after ischemic brain injury. 2897 25

Hepatocellular carcinoma (HCC) results in large amounts of deaths each year worldwide. To develop more effective treatments for HCC, it is very necessary to define the molecular mechanisms in hepatocarcinogenesis. Mixed lineage kinase (MLK)-4 is a member of the MLK family of mitogen-activated protein kinase kinase kinases, and modulates different cellular responses. However, its role in the meditation of HCC progression remains unclear. In the study, we found that MLK4 was over-expressed in tumor samples of HCC patients. High MLK4 expression was significantly associated with shorter overall survival in HCC. Knockdown of MLK4 inhibited HCC cell proliferation and metastasis, which was partly through reducing matrix metalloproteinase (MMP)-13, MMP2, enhancer of zeste homolog 2 (EZH2) and Vimentin expressions. Apoptosis was significantly induced by MLK4 knockdown in HCC cells via decreasing Bcl-2 and increasing cleaved poly (ADP-ribose) polymerase (PARP), Caspase-7 and -3 expression levels. In addition, MLK4 silence led to a significant reactive oxygen species (ROS) production in liver cancer cells, accompanied with elevated expression of phosphorylated p38, c-Jun N-terminal kinase (JNK) and ERK1/2. Notably, reducing ROS generation and blocking MAPKs (p38/JNK/ERK1/2) signaling markedly abrogated MLK4 knockdown-induced apoptosis in HCC cells. Moreover, MLK4 silence-prevented metastasis was also rescued by scavenging ROS generation and repressing MAPKs pathway. In vivo, injection of MLK4 siRNA markedly inhibited liver tumor growth in xenograft models, and MLK4 knockdown reduced HCC lung metastasis. Together, our study indicated the essential function of MLK4 in HCC progression, providing crucial therapeutic hypothesis for the prevention of hepatocellular carcinoma.
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PMID:Decrease of MLK4 prevents hepatocellular carcinoma (HCC) through reducing metastasis and inducing apoptosis regulated by ROS/MAPKs signaling. 3193 24