p27 deregulation by Skp2 overexpression induced by the JAK2V617 mutation.
Janus kinase 2 (JAK2) V617F mutation has been regarded as the major cause of myeloproliferative disorders (MPD). However, the mechanisms of abnormal cell growth by JAK2V617F have not been elucidated. In this study, cell cycle regulatory protein expression was analyzed using JAK2V617F-Ba/F3 and mock-Ba/F3. JAK2V617F-Ba/F3, but not mock-Ba/F3, showed IL-3 independent cell growth and constitutive STATs activation. Deregulation of p27(Kip1), the cell cycle regulator at the G1 to S transition, was observed in JAK2V617F-Ba/F3 but not in mock-control. p27(Kip1) deregulation was not due to p27(Kip1) mRNA level but due to high Skp2 expression, a subunit of ubiquitin E3 ligase, through the STAT binding in the Skp2 promoter. Like JAK2V617F overexpression, constitutively active STAT5 or STAT3 induced aberrant p27(Kip1) expression of Ba/F3 cells. Similar findings were observed in BCR/ABL-transfected Ba/F3. Our results elucidate the regulatory mechanism by which JAK2V617F modulates Skp2 gene expression through the STAT transcription factors.
Nagoya University Graduate School of Medicine, Nagoya University School of Health Sciences, Nagoya, Japan.
A
A
Furuhata
A
A
Kimura
K
K
Shide
K
K
Shimoda
M
M
Murakami
H
H
Ito
S
S
Gao
K
K
Yoshida
Y
Y
Tagawa
K
K
Hagiwara
A
A
Takagi
T
T
Kojima
M
M
Suzuki
A
A
Abe
T
T
Naoe
T
T
Murate
D000818:Animals; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D007377:Interleukin-3 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics*; D050791:STAT Transcription Factors / Q000378:metabolism*
D007377:Interleukin-3; D044786:S-Phase Kinase-Associated Proteins; D050791:STAT Transcription Factors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D053614:Janus Kinase 2