Requirement of protein kinase (Krs/MST) activation for MT-21-induced apoptosis.
Fas is a well characterized apoptosis-inducing factor. One of our synthetic compounds, MT-21, induced apoptosis in human leukemia HL-60 cells similar to Fas. MT-21 activated caspase-3, an important cysteine aspartic protease for apoptosis induction. MT-21 also activated c-Jun-NH2-terminal kinase (JNK), a member of mitogen activated protein kinase (MAPK) superfamily that is involved in the regulation of cell growth, differentiation and cell death. Moreover, MT-21 treatment resulted in the activation of a 36 kDa kinase which uses myelin basic protein (MBP) as a substrate. However, MAPK and p38 were not activated by treatment with MT-21. The 36 kDa MBP kinase was shown to be a proteolytic product derived from the Krs protein with a molecular weight of 60 kDa. The Krs protein is a Ser/Thr protein kinase whose activity is enhanced by digestion of its C-terminal regulatory domain by caspase-3. When a kinase-inactive mutant form of Krs protein was overexpressed in HL-60 cells, JNK activation and apoptosis induction by MT-21 were suppressed. Furthermore, overexpression of dominant negative c-Jun also suppressed apoptosis induction by MT-21. These findings indicate that MT-21 induces apoptosis by the activation of JNK via the Krs protein, which is activated by caspase cleavage.
Watabe
M
M
Laboratory of Antibiotics, The Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Kakeya
H
H
Osada
H
H
D019943:Amino Acid Substitution; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein; D016758:Genes, jun; D018922:HL-60 Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008562:Membrane Glycoproteins / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases; D016297:Mutagenesis, Site-Directed; D004676:Myelin Basic Protein / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction / Q000187:drug effects*; D020298:U937 Cells / Q000187:drug effects / Q000201:enzymology; D019014:fas Receptor / Q000502:physiology; D000099317:Hippo Kinases
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D053148:Caspase 3; D020169:Caspases; D004273:DNA, Neoplasm; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D004676:Myelin Basic Protein; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011758:Pyrroles; D017382:Reactive Oxygen Species; D000090742:Serine-Threonine Kinase 3; D019014:fas Receptor; C505661:FASLG protein, human; C121809:MT 21; C095566:STK4 protein, human; D000099317:Hippo Kinases; C097835:STK3 protein, human; C505407:CASP3 protein, human