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INTRODUCTION ERK, JNK and p38 MAPK are vital and central elements of the MAPK family. They help in the transmission of those signals which originate due to stress, cytokines or growth factors. ERK is the final enzyme of the MAPK pathway which transmits signals into the nucleus. The ultimate effect is the activation of the transcription factors which influence the expression of genes. The transcription factors include AP-1 and NF-?B. Stress specifically activates JNK kinase. Sophisticated screening of the screening library led to the discovery of SP600125 which inhibits JNK. STELLATE CELLS OF PANCREAS INHIBITED FROM GETTING ACTIVATED BY SP600125 During injury to pancreas, the stellate cells usually become highly proliferative and smooth muscles start expressing actin protein (alpha type). This transformation into myofibroblast type cells help in the synthesis of extracellular components. This stimulates inflammation and fibrosis within the pancreas. An anthrapyrazole derivative SP600125 inhibits JNK, when stellate cells of pancreas are activated. The effect of this inhibitor on synthesis of collagen, production of chemokine and proliferation was analyzed. When freshly cultured stellate cells were administered with SP600125, the activity of IL- 1? was suppressed. 46- kDa and 54-kDa JNK were both activated in the presence of IL- 1? and PDGF-BB stimulates the activation of only 46-kDa JNK. SP600125 inhibited the activation of both the isoforms of JNK and activator protein-1. This inhibitor had no effect on the p38 MAP Kinase or ERK. The proliferation of the cells which is usually stimulated by PDGF is inhibited. The collagen synthesis was also controlled. On the whole it does not control the transformation but checks the proliferation [1]. CDK1 LEVELS ARE CONTROLLED BY SP600125 A proper cell cycle involves the replication of DNA (synthesis) which is followed by proper cell division that is mitosis. When these steps are not properly regulated the DNA replication continues to produce multiple copies of DNA. During endoreplication the cell escapes the stage of cell division as a result of which genome attains a polyploid nature. When the cells get subjected to endoreplication during the Gap2 phase, the cell skips all the vital steps involved during the mitosis. JNK inhibitor SP600125 does not allow the cells to enter into the mitotic stage and stimulates the process of endoreplication during the Gap2 stage. This activity is independent of its inhibition of JNK. To analyze this effect SP600125 was administered along with U0126 (MEK1/2 inhibitor) within HCT116 cells. SP600125 showed significant effect in this line in comparison to other inhibitors and checks the phosphorylation of Cdk1. An increased activity of Cdk2 and inhibition of Cdk1 together stimulate the process of endoreplication [2]. SP600125 MAKES GC-RESISTANT CELLS SENSITIVE TO DEX Glucocorticoids are well known for their stimulation of apoptosis in case of different malignancies. MAPK alters the glucocorticoid sensitivity. CEM-C1-15 cells show a high JNK and ERK activity. These cells were subjected to JNK, ERK inhibitors along with mTOR inhibitor rapamycin. These data suggest that glucocorticoids influence apoptosis through MAPK pathway [3]. CONCLUSION In summary SP600125 is an efficient inhibitor of JNK which controls the stress and inflammatory response. It competes with ATP and controls the LPS induced expression of TNF-? [4] REFERENCES 1. Masamune A, Kikuta K, et al. A c-Jun NH2-Terminal Kinase Inhibitor SP600125 (Anthra[1,9-cd]pyrazole-6 (2H)-one) Blocks Activation of Pancreatic Stellate Cells. JPET 2004 Aug; 310(2): 520-527. 2. Kim JA, Lee J, et al. SP600125 suppresses Cdk1 and induces endoreplication directly from G2 phase, independent of JNK inhibition. Oncogene 2010 March 18; 29: 1702-1716. 3. Miller AL, Garza AS, et al. Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells. Cancer Cell International 2007; 7:3. 4. Bennett BL, Sasaki DT, et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. PNAS 2001 Nov 20; 98(24): 13681-13686. Related Posts: GDC-0879 – TARGETS B-RAF AND CONTROLS A VARIETY OF CANCERS SORAFENIB – EFFECTIVE AGAINST MULTIPLE KINASES Related to SP600125 – A JNK INHIBITOR SP600125 – AN INHIBITOR WITH ANTHRAPYRAZOLONE RING INTRODUCTION Inflammatory diseases are associated with an increase in immune proteins which make the pathology of the disease irreversible. Some transcription factors stimulate multiple genes ... SP600125 – AN EFFICIENT INHIBITOR OF JNKs INTRODUCTION JNK whose full name is Jun N-terminal kinase, is activated under stress. The stress can be an outcome of different reasons like endotoxins produced ... 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