Histone H1(S)-3 phosphorylation in Ha-ras oncogene-transformed mouse fibroblasts.
Phosphorylation of linker histone H1(S)-3 (previously named H1b) and core histone H3 is elevated in mouse fibroblasts transformed with oncogenes or constitutively active mitogen-activated protein kinase (MAPK) kinase (MEK). H1(S)-3 phosphorylation is the only histone modification known to be dependent upon transcription and replication. Our results show that the increased amounts of phosphorylated H1(S)-3 in the oncogene Ha-ras-transformed mouse fibroblasts was a consequence of an elevated Cdk2 activity rather than the reduced activity of a H1 phosphatase, which our studies suggest is PP1. Induction of oncogenic ras expression results in an increase in H1(S)-3 and H3 phosphorylation. However, in contrast to the phosphorylation of H3, which occurred immediately following the onset of Ras expression, there was a lag of several hours before H1(S)-3 phosphorylation levels increased. We found that there was a transient increase in the levels of p21(cip1), which inhibited the H1 kinase activity of Cdk2. Cdk2 activity and H1(S)-3 phosphorylated levels increased after p21(cip1) levels declined. Our studies suggest that persistent activation of the Ras-MAPK signal transduction pathway in oncogene-transformed cells results in deregulated activity of kinases phosphorylating H3 and H1(S)-3 associated with transcribed genes. The chromatin remodelling actions of these modified histones may result in aberrant gene expression.
Chadee
Deborah N
DN
Manitoba Institute of Cell Biology, 675 McDermot Avenue, Winnipeg, Manitoba, R3E 0V9 Canada.
Peltier
Cheryl P
CP
Davie
James R
JR
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002455:Cell Division; D002460:Cell Line; D002461:Cell Line, Transformed; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts; D005786:Gene Expression Regulation; D011905:Genes, ras; D006657:Histones / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D006657:Histones; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases