Related Experiment Video

Updated: Jun 24, 2026

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

p27 deregulation by Skp2 overexpression induced by the JAK2V617 mutation

A Furuhata1, A Kimura, K Shide

  • 1Nagoya University Graduate School of Medicine, Nagoya University School of Health Sciences, Nagoya, Japan.

Biochemical and Biophysical Research Communications
|April 15, 2009
PubMed

Insights

The Janus kinase 2 (JAK2) V617F mutation drives myeloproliferative disorders by increasing Skp2 expression. This elevates ubiquitin E3 ligase activity, leading to cell cycle deregulation and abnormal cell growth.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • The Janus kinase 2 (JAK2) V617F mutation is a primary driver of myeloproliferative disorders (MPDs).
  • Mechanisms underlying JAK2V617F-induced abnormal cell growth remain incompletely understood.
  • Cell cycle regulation is frequently disrupted in malignant transformations.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which JAK2V617F promotes abnormal cell proliferation.
  • To investigate the role of cell cycle regulatory proteins in JAK2V617F-driven MPDs.
  • To identify key molecular targets involved in JAK2V617F-mediated oncogenesis.

Main Methods:

  • Comparative analysis of cell cycle regulatory protein expression in JAK2V617F-Ba/F3 and mock-Ba/F3 cells.
  • Assessment of IL-3 independent cell growth and STATs activation.
  • Investigation of p27(Kip1) and Skp2 expression levels and their regulatory pathways.
  • Analysis of STAT binding to the Skp2 promoter.

Main Results:

  • JAK2V617F-Ba/F3 cells exhibited IL-3 independent growth and constitutive STATs activation.
  • Deregulation of p27(Kip1) was observed in JAK2V617F-Ba/F3 cells, linked to elevated Skp2 expression.
  • Skp2 upregulation resulted from STAT binding to the Skp2 promoter, not altered p27(Kip1) mRNA levels.
  • Constitutively active STAT5, STAT3, and BCR/ABL also induced aberrant p27(Kip1) expression.

Conclusions:

  • JAK2V617F promotes abnormal cell growth by modulating Skp2 gene expression via STAT transcription factors.
  • This mechanism leads to p27(Kip1) deregulation and cell cycle disruption in MPDs.
  • Targeting the JAK2-STAT-Skp2 pathway may offer therapeutic strategies for MPDs.

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...