Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death of mitogen-activated protein (MAP) kinase family members, including ERK (extracellular signal-regulated kinase), JNK (c-JUN NH2-terminal protein kinase), and p38, were examined after withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromocytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs. The effects of dominant-interfering or constitutively activated forms of various components of the JNK-p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of apoptosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be important in determining whether a cell survives or undergoes apoptosis.

https://science.sciencemag.org/content/sci/270/5240/1326.full.pdf

Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis

Biologic basis for interleukin-1 in disease

Mitogen-activated protein (MAP) kinases comprise a family of ubiquitous proline-directed, protein-serine/threonine kinases, which participate in signal transduction pathways that control intracellular events including acute responses to hormones and major developmental changes in organisms. MAP kinases lie in protein kinase cascades. This review discusses the regulation and functions of mammalian MAP kinases. Nonenzymatic mechanisms that impact MAP kinase functions and findings from gene disruption studies are highlighted. Particular emphasis is on ERK1/2.

/pdf/mitogen-activated-protein-map-kinase-pathways-regulation-and-3nsauvepr2.pdf

Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions.

Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) that control a vast array of physiological processes. These enzymes are regulated by a characteristic phosphorelay system in which a series of three protein kinases phosphorylate and activate one another. The extracellular signal-regulated kinases (ERKs) function in the control of cell division, and inhibitors of these enzymes are being explored as anticancer agents. The c-Jun amino-terminal kinases (JNKs) are critical regulators of transcription, and JNK inhibitors may be effective in control of rheumatoid arthritis. The p38 MAPKs are activated by inflammatory cytokines and environmental stresses and may contribute to diseases like asthma and autoimmunity.

https://science.sciencemag.org/content/sci/298/5600/1911.full.pdf

Mitogen-Activated Protein Kinase Pathways Mediated by ERK, JNK, and p38 Protein Kinases

PD 098059 Is a Specific Inhibitor of the Activation of Mitogen-activated Protein Kinase Kinase in Vitro and in Vivo

Production of interleukin-1 and tumour necrosis factor from stimulated human monocytes is inhibited by a new series of pyridinyl-imidazole compounds. Using radiolabelled and radio-photoaffinity-labelled chemical probes, the target of these compounds was identified as a pair of closely related mitogen-activated protein kinase homologues, termed CSBPs. Binding of the pyridinyl-imidazole compounds inhibited CSBP kinase activity and could be directly correlated with their ability to inhibit cytokine production, suggesting that the CSBPs are critical for cytokine production.

A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.

C-H Activation and Palladium Migration within Biaryls under Heck Reaction Conditions

When combined with an appropriate nucleophilic component, 1,2- and 1,3-cyclic sulfamidates function as versatile precursors to a range of substituted and enantiopure heterocyclic classes. Functionalised enolates provide a direct entry to C-3 functionalised lactams, as exemplified by total syntheses of (−)-aphanorphine, (+)-laccarin and (−)-paroxetine. Heteroatom nucleophiles, such as thiol esters, amino esters and bromo phenols, provide concise access to a range of enantiomerically pure thiomorpholine, piperazine and benzofused heterocyclic scaffolds. The latter methodology enables a facile synthesis of the antibacteriocidal agent levofloxacin.

Timothy Gallagher

Papers

A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.

C-H Activation and Palladium Migration within Biaryls under Heck Reaction Conditions

N-Heterocycle construction via cyclic sulfamidates. Applications in synthesis

Enantiopure 1,4-benzoxazines via 1,2-cyclic sulfamidates. Synthesis of levofloxacin.

Direct and regioselective C-H alkenylation of tetrahydropyrido[1,2-a]pyrimidines.