Apoptosis signal-regulating kinase 1(ASK1) is a member of MAP kinase kinase kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. It has been found to be involved in cancer, diabetes, cardiovascular and neurodegenerative diseases.
An overview of apoptosis signal-regulating kinase 1 (ASK1)
Apoptosis signal-regulating kinase 1 (ASK1) acts as a part of mitogen-activated protein kinase pathway and belongs to mitogen-activated protein (MAP) kinase kinase kinase family. It is located on the upstream of P38 and c-JUN N-terminal kinase (JNK) and activated by phosphorylation. Many kinds of stress injury and proinflammatory factors, such as H202, TNF-α, ischemia-reperfusion and chemotherapeutic drugs can activate ASK1. And activating ASK1 can activate MKK3/MKK6-P38 and MKK-4/MKK7-JNK kinase pathway, which responds to stress or induce cell apoptosis. What's more, it has been found to be involved in cancer, diabetes, cardiovascular and neurodegenerative diseases.
Inhibition of apoptosis signal-regulating kinase 1 (ASK1)
Selonsertib (GS-4997) is a highly selective and effective ASK1 inhibitor, which has potential anti-inflammatory, antitumor and anti-fibrosis activities. NQDI-1 is also an ASK1 inhibitor that can weaken acute ischemic kidney damage by regulating oxidative stress reaction and cell death.
Apoptosis signal-regulating kinase 1 (ASK1) and diseases
Cardiac hypertrophy is a basic response to the common clinical diseases, such as hypertension, valvular disease, acute myocardial infarction and congenital heart disease, which is an independent risk factor affecting the mortality and morbidity of cardiovascular diseases. ASK1 participates in cell growth, differentiation and apoptosis. Many experiments have proved that in many hypertrophic stimulation induced cardiac hypertrophy, such as ROS, TNF, Ca2+/protein kinase, small GTP binding protein, G protein coupling receptor agonist, and distraction stimulation, ASK1 is the key material on signal transduction pathway. For example, the ASK1 gene knockout mice compared to normal mice, the heart structure and function were normal, only mild myocardial and peripheral tissue fibrosis, and the number of apoptotic myocardium cells decreased significantly in the overload model of left coronary artery ligation myocardial infarction and thoracic aortic coarctation. It is indicated that ASK1 plays an important role in regulating left ventricular remodeling under the condition of myocardial infarction and overload.
Qiu M, et al. (2007). Apoptosis signal regulation kinase 1 and cardiac hypertrophy research progress. Advances in Cardiovascular Diseases.