A prospective, randomised, double-blind, placebo-controlled, parallel group dose ranging study in asthma patients in Iceland to assess the safety, tolerability and efficacy of the MLK inhibitor, CEP-1347

Start Date04 May 2005

Sponsor / Collaborator

deCODE Genetics ehf

NCT00040404 / TerminatedPhase 2/3

A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study to Assess the Efficacy and Safety of CEP-1347 in Patients With Parkinson's Disease

The purpose of this study is to establish safety for CEP-1347 and to determine an efficacious dose in the treatment of Parkinson's disease.

Start Date01 Mar 2002

Sponsor / Collaborator

Cephalon, Inc.

[+2]

100 Clinical Results associated with MLK subfamily

100 Translational Medicine associated with MLK subfamily

0 Patents (Medical) associated with MLK subfamily

916

Literatures (Medical) associated with MLK subfamily

31 Dec 2024·International Journal of Hyperthermia

Deregulated JNK signaling enhances apoptosis during hyperthermia

Article

Author: Sato, Shinichi ; Nakagawa, Keiichi ; Miyagawa, Kiyoshi ; Yoshizaki, Ayumi ; Hosoya, Noriko ; Terunuma, Hiroshi ; Enomoto, Atsushi ; Fukasawa, Takemichi

PURPOSEc-Jun N-terminal kinases (JNKs) comprise a subfamily of mitogen-activated protein kinases (MAPKs). The JNK group is known to be activated by a variety of stimuli. However, the molecular mechanism underlying heat-induced JNK activation is largely unknown. The aim of this study was to clarify how JNK activity is stimulated by heat.METHODS AND MATERIALSThe expression levels of various MAPK members in HeLa cells, with or without hyperthermia treatment, were evaluated via western blotting. The kinase activity of MAPK members was assessed through in vitro kinase assays. Cell death was assessed in the absence or presence of siRNAs targeting MAPK-related members.RESULTSHyperthermia decreased the levels of MAP3Ks, such as ASK1 and MLK3 which are JNK kinase kinase members, but not those of the downstream MAP2K/SEK1 and MAPK/JNK. Despite the reduced or transient phosphorylation of ASK1, MLK3, or SEK1, downstream JNK was phosphorylated in a temperature-dependent manner. In vitro kinase assays demonstrated that heat did not directly stimulate SEK1 or JNK. However, the expression levels of DUSP16, a JNK phosphatase, were decreased upon hyperthermia treatment. DUSP16 knockdown enhanced the heat-induced activation of ASK1-SEK1-JNK pathway and apoptosis.CONCLUSIONJNK was activated in a temperature-dependent manner despite reduced or transient phosphorylation of the upstream MAP3K and MAP2K. Hyperthermia-induced degradation of DUSP16 may induce activation of the ASK1-SEK1-JNK pathway and subsequent apoptosis.

01 Dec 2024·Cellular and Molecular Life Sciences

Disrupting PIAS3-mediated SUMOylation of MLK3 ameliorates poststroke neuronal damage and deficits in cognitive and sensorimotor behaviors

Article

Author: Hu, Lulu ; Shao, Mengwen ; Chen, Rourou ; Zhang, Bingge ; Meng, Li ; Xu, Yan ; Jiang, Yu ; Wang, Baixue ; Du, Caiping ; Li, Meng

AbstractActivated small ubiquitin-like modifiers (SUMOs) have been implicated in neuropathological processes following ischemic stroke. However, the target proteins of SUMOylation and their contribution to neuronal injury remain to be elucidated. MLK3 (mixed-lineage kinase 3), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, is a critical regulator of neuronal lesions following cerebral ischemia. Here, we found that SUMOylation of MLK3 increases in both global and focal ischemic rodent models and primary neuronal models of oxygen and glucose deprivation (OGD). SUMO1 conjugation at the Lys401 site of MLK3 promoted its activation, stimulated its downstream p38/c-Jun N-terminal kinase (JNK) cascades, and led to cell apoptosis. The interaction of MLK3 with PIAS3, a SUMO ligase, was elevated following ischemia and reperfusion. The PINIT domain of PIAS3 was involved in direct interactions with MLK3. Overexpression of the PINIT domain of PIAS3 disrupted the MLK3-PIAS3 interaction, inhibited SUMOylation of MLK3, suppressed downstream signaling, and reduced cell apoptosis and neurite damage. In rodent ischemic models, the overexpression of the PINIT domain reduced brain lesions and alleviated deficits in learning, memory, and sensorimotor functions. Our findings demonstrate that brain ischemia-induced MLK3 SUMOylation by PIAS3 is a potential target against poststroke neuronal lesions and behavioral impairments.

01 Nov 2024·Cell Death & Differentiation

FRMD6 determines the cell fate towards senescence: involvement of the Hippo-YAP-CCN3 axis

Article

Author: Kim, Eung-Gook ; Kim, Jaehong ; Lee, Su Jin ; Baek, Minwoo ; Lee, Ok-Jun ; Shin, Eun-Young ; Park, Jung-Jin ; Nam, Seungyoon ; Kim, Jin Young

AbstractCellular senescence, a hallmark of aging, is pathogenically linked to the development of aging-related diseases. This study demonstrates that FRMD6, an upstream component of the Hippo/YAP signaling cascade, is a key regulator of senescence. Proteomic analysis revealed that FRMD6 is upregulated in senescent IMR90 fibroblasts under various senescence-inducing conditions. Silencing FRMD6 mitigated the senescence of IMR90 cells, suggesting its requirement in senescence. Conversely, the overexpression of FRMD6 alone induced senescence in cells and in lung tissue, establishing a causal link. The elevated FRMD6 levels correlated well with increased levels of the inhibitory phosphorylated YAP/TAZ. We identified cellular communication network factor 3 (CCN3), a key component of the senescence-associated secretory phenotype regulated by YAP, whose administration attenuated FRMD6-induced senescence in a dose-dependent manner. Mechanistically, FRMD6 interacted with and activated MST kinase, which led to YAP/TAZ inactivation. The expression of FRMD6 was regulated by the p53 and SMAD transcription factors in senescent cells. Accordingly, the expression of FRMD6 was upregulated by TGF-β treatment that activates those transcription factors. In TGF-β-treated IMR90 cells, FRMD6 mainly segregated with p21, a senescence marker, but rarely segregated with α-SMA, a myofibroblast marker, which suggests that FRMD6 has a role in directing cells towards senescence. Similarly, in TGF-β-enriched environments, such as fibroblastic foci (FF) from patients with idiopathic pulmonary fibrosis, FRMD6 co-localized with p16 in FF lining cells, while it was rarely detected in α-SMA-positive myofibroblasts that are abundant in FF. In sum, this study identifies FRMD6 as a novel regulator of senescence and elucidates the contribution of the FRMD6-Hippo/YAP-CCN3 axis to senescence.

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