TY - JOUR
T1 - p27 deregulation by Skp2 overexpression induced by the JAK2V617 mutation
AU - Furuhata, A.
AU - Kimura, A.
AU - Shide, K.
AU - Shimoda, K.
AU - Murakami, M.
AU - Ito, H.
AU - Gao, S.
AU - Yoshida, K.
AU - Tagawa, Y.
AU - Hagiwara, K.
AU - Takagi, A.
AU - Kojima, T.
AU - Suzuki, M.
AU - Abe, A.
AU - Naoe, T.
AU - Murate, T.
PY - 2009/6/12
Y1 - 2009/6/12
N2 - 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 p27Kip1, the cell cycle regulator at the G1 to S transition, was observed in JAK2V617F-Ba/F3 but not in mock-control. p27Kip1 deregulation was not due to p27Kip1 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 p27Kip1 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.
AB - 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 p27Kip1, the cell cycle regulator at the G1 to S transition, was observed in JAK2V617F-Ba/F3 but not in mock-control. p27Kip1 deregulation was not due to p27Kip1 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 p27Kip1 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.
UR - http://www.scopus.com/inward/record.url?scp=67349223963&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67349223963&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2009.04.015
DO - 10.1016/j.bbrc.2009.04.015
M3 - Article
C2 - 19364496
AN - SCOPUS:67349223963
SN - 0006-291X
VL - 383
SP - 411
EP - 416
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -