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Cytoplasmic Mislocalization of p27Kip1 Protein Is Associated with Constitutive Phosphorylation of Akt or Protein Kinase B and Poor Prognosis in Acute Myelogenous Leukemia

 Yoo Hong Min  ;  June-Won Cheong  ;  Mark Hong Lee  ;  Yun Woong Ko  ;  Jee Sook Hahn  ;  Seung Tae Lee  ;  Ju In Eom  ;  Ji Yeon Kim 
 Cancer Research, Vol.64(15) : 5225-5231, 2004 
Journal Title
 Cancer Research 
Issue Date
Acute Disease ; Adolescent ; Adult ; Aged ; Biomarkers, Tumor ; Cell Cycle ; Cell Cycle Proteins/metabolism* ; Cell Nucleus/metabolism ; Cyclin-Dependent Kinase Inhibitor p27 ; Cytoplasm/metabolism* ; Enzyme Inhibitors/metabolism* ; Female ; Genes, Dominant ; Genes, Tumor Suppressor ; Humans ; Leukemia, Myeloid/metabolism* ; Leukemia, Myeloid/pathology ; Leukemia, Myeloid/therapy ; Male ; Middle Aged ; Phosphorylation ; Prognosis ; Protein Transport ; Protein-Serine-Threonine Kinases/metabolism* ; Protein-Tyrosine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism* ; Proto-Oncogene Proteins c-akt ; Subcellular Fractions ; Survival Rate ; Tumor Suppressor Proteins/metabolism* ; U937 Cells
Cyclin-dependent kinase inhibitor p27Kip1 functions at the nuclear level by binding to cyclin E/cyclin-dependent kinase-2. It was shown that Akt or protein kinase B (Akt/PKB)-dependent phosphorylation of p27Kip1 led to the cytoplasmic mislocalization of p27Kip1, suggesting the potential abrogation of its activity. Here, we evaluated the localization of p27Kip1 protein in leukemic blasts in relation to Akt/PKB phosphorylation and clinical outcomes in acute myelogenous leukemia (AML). Western blot analysis of the nuclear and cytoplasmic fractions revealed a heterogenous localization pattern of p27Kip1 in AML. Cytoplasmic mislocalization of p27Kip1 was significantly associated with the constitutive serine473 Akt/PKB phosphorylation in AML cells (P < 0.05). Transfection of U937 cells with an expression construct encoding the constitutively active form of Akt/PKB resulted in a remarkable increase in the levels of cytoplasmic p27Kip1. Whereas the transfection of U937 cells with a construct encoding dominant-negative Akt/PKB resulted in a recovery of nuclear localization of p27Kip1. Both the disease-free survival and overall survival are significantly shorter in AML cases with high cytoplasmic to nuclear ratio of p27Kip1 localization compared with the cases with low cytoplasmic to nuclear ratio (P = 0.0353, P = 0.0023, respectively). Multivariate analysis indicated that the cytoplasmic to nuclear ratio of p27Kip1 localization was an independent prognostic variable for both disease-free survival and overall survival (P = 0.043, P = 0.008, respectively). These findings additionally extend our understanding of the role of p27Kip1 in AML, and buttress the case of p27Kip1 mislocalization as a prognostic indicator and Akt/PKB/p27Kip1 pathway as a ready target for antileukemia therapy.
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1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Ko, Yun Woong(고윤웅)
Kim, Ji Yeon(김지연)
Min, Yoo Hong(민유홍) ORCID logo https://orcid.org/0000-0001-8542-9583
Eom, Ju In(엄주인)
Lee, Seung Tae(이승태)
Cheong, June-Won(정준원) ORCID logo https://orcid.org/0000-0002-1744-0921
Hahn, Jee Sook(한지숙)
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