Cot, a novel kinase of histone H3, induces cellular transformation through up-regulation of c-fos transcriptional activity.
Post-translational modification of histones is critical for gene expression, mitosis, cell growth, apoptosis, and cancer development. Thus, finding protein kinases that are responsible for the phosphorylation of histones at critical sites is considered an important step in understanding the process of histone modification. The serine/threonine kinase Cot is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family. We show here that Cot can phosphorylate histone H3 at Ser-10 in vivo and in vitro, and that the phosphorylation of histone H3 at Ser-10 is required for Cot-induced cell transformation. We found that activated Cot is recruited to the c-fos promoter resulting in increased activator protein-1 (AP-1) transactivation. The formation of the Cot-c-fos promoter complex was also apparent when histone H3 was phosphorylated at Ser-10. Furthermore, the use of dominant negative mutants of histone H3 revealed that Cot was required for phosphorylation of histone H3 at Ser-10 to induce neoplastic cell transformation. These results revealed an important function of Cot as a newly discovered histone H3 kinase. Moreover, the transforming ability of Cot results from the coordinated activation of histone H3, which ultimately converges on the regulation of the transcriptional activity of the c-fos promoter, followed by AP-1 transactivation activity.
Choi
Hong Seok
HS
Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA.
Kang
Bong Seok
BS
Shim
Jung-Hyun
JH
Cho
Yong-Yeon
YY
Choi
Bu Young
BY
Bode
Ann M
AM
Dong
Zigang
Z
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction; D016762:Genes, fos; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D014158:Transcription, Genetic; D014466:Ultraviolet Rays; D015854:Up-Regulation
D017931:DNA Primers; D006657:Histones; D017346:Protein Serine-Threonine Kinases