Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MLK4 is a member of the mixed-lineage family of kinases that regulate the JNK, p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in various human cancers, including frequently in colorectal cancer, where their function and pathobiological importance have been uncertain. In this study, we assessed the functional consequences of MLK4 mutations in colon tumorigenesis. Biochemical data indicated that a majority of MLK4 mutations are loss-of-function (LOF) mutations that can exert dominant-negative effects. In seeking to understand the abrogated activity of these mutants, we elucidated a new MLK4 catalytic domain structure. To determine whether MLK4 is required to maintain tumorigenic phenotypes, we reconstituted its signaling axis in colon cancer cells harboring MLK4-inactivating mutations. We found that restoring MLK4 activity reduced cell viability, proliferation, and colony formation in vitro and delayed tumor growth in vivo. Mechanistic investigations established that restoring the function of MLK4 selectively induced the JNK pathway and its downstream targets, cJUN, ATF3, and the cyclin-dependent kinase inhibitors CDKN1A and CDKN2B. Our work indicates that MLK4 is a novel tumor-suppressing kinase harboring frequent LOF mutations that lead to diminished signaling in the JNK pathway and enhanced proliferation in colon cancer.
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PMID:Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis. 2663 68

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