PMID:20921231

Citation	Wen, W, Zhu, F, Zhang, J, Keum, YS, Zykova, T, Yao, K, Peng, C, Zheng, D, Cho, YY, Ma, WY, Bode, AM and Dong, Z (2010) MST1 promotes apoptosis through phosphorylation of histone H2AX. J. Biol. Chem. 285:39108-16
Abstract	MST1 (mammalian STE20-like kinase 1) is a serine/threonine kinase that is cleaved and activated by caspases during apoptosis. Overexpression of MST1 induces apoptotic morphological changes such as chromatin condensation, but the mechanism is not clear. Here we show that MST1 induces apoptotic chromatin condensation through its phosphorylation of histone H2AX at Ser-139. During etoposide-induced apoptosis in Jurkat cells, the cleavage of MST1 directly corresponded with strong H2AX phosphorylation. In vitro kinase assay results showed that MST1 strongly phosphorylates histone H2AX. Western blot and kinase assay results with a mutant S139A H2AX confirmed that MST1 phosphorylates H2AX at Ser-139. Direct binding of MST1 and H2AX can be detected when co-expressed in HEK293 cells and was also confirmed by an endogenous immunoprecipitation study. When overexpressed in HeLa cells, both the MST1 full-length protein and the MST1 kinase domain (MST1-NT), but not the kinase-negative mutant (MST1-NT-KN), could induce obvious endogenous histone H2AX phosphorylation. The caspase-3 inhibitor benzyloxycarbonyl-DEVD-fluoromethyl ketone (Z-DEVD-fmk) attenuates phosphorylation of H2AX by MST1 but cannot inhibit MST1-NT-induced histone H2AX phosphorylation, indicating that cleaved MST1 is responsible for H2AX phosphorylation during apoptosis. Histone H2AX phosphorylation and DNA fragmentation were suppressed in MST1 knockdown Jurkat cells after etoposide treatment. Taken together, our data indicated that H2AX is a substrate of MST1, which functions to induce apoptotic chromatin condensation and DNA fragmentation.
Links	PubMed PMC2998151 Online version:10.1074/jbc.M110.151753
Keywords	Apoptosis; Chromatin/chemistry; DNA Fragmentation; Etoposide/pharmacology; Gene Expression Regulation, Neoplastic; HEK293 Cells; HeLa Cells; Hepatocyte Growth Factor/metabolism; Histones/chemistry; Histones/metabolism; Humans; Jurkat Cells; Phosphorylation; Proto-Oncogene Proteins/metabolism; Serine/chemistry
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:HGFL		GO:0035978: histone H2A-S139 phosphorylation	ECO:0000314:		P		A kinase assay showed that MST1 strongly phosphorylated H2AX and western blot analysis showed that MST1 phosphorylated H2AX at ser-139 (Figure 2A and 2B).	complete CACAO 12198
HUMAN:HGFL		GO:0035978: histone H2A-S139 phosphorylation	ECO:0000315:		P		Comparing wild type H2AX and mutant H2AX-S139A, the author found that phosphorylation of the mutant H2AX-S139A by MST1 was dramatically decreased confirming that MST1 phosphorylates at S139 (Figure 2C and 2D).	complete CACAO 12211

References

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