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Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis
T Shirogane1, T Fukada, J M Muller
1Division of Molecular Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine, Suita, Japan.
Abstract:
The activation of STAT3 by the cytokine receptor gp130 is required for both the G1 to S cell cycle transition and antiapoptosis. We found that Pim-1 and Pim-2 are targets for the gp130-mediated STAT3 signal. Expression of a kinase-defective Pim-1 mutant attenuated gp130-mediated cell proliferation. Constitutive expression of Pim-1 together with c-myc, another STAT3 target, fully compensated for loss of the STAT3-mediated cell cycle progression, antiapoptosis, and bcl-2 expression. We also identified valosine-containing protein (VCP) as a target gene for the Pim-1-mediated signal. Expression of a mutant VCP led cells to undergo apoptosis. These results indicate that Pim-family proteins play crucial roles in gp130-mediated cell proliferation and explain the synergy between Pim and c-Myc proteins in cell proliferation and lymphomagenesis.
Insights
Signal transducer and activator of transcription 3 (STAT3) activation by gp130 is crucial for cell cycle progression and survival. Pim-family proteins are key mediators in this pathway, working synergistically with c-Myc to drive cell proliferation and lymphomagenesis.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Signal transducer and activator of transcription 3 (STAT3) activation by the cytokine receptor gp130 is essential for cell cycle progression and apoptosis resistance.
- Understanding the downstream effectors of this pathway is critical for comprehending cell proliferation and oncogenesis.
Purpose of the Study:
- To identify and characterize downstream targets of the gp130-STAT3 signaling pathway.
- To elucidate the roles of Pim-family kinases and their targets in cell proliferation and survival.
- To investigate the synergistic interaction between Pim and c-Myc in lymphomagenesis.
Main Methods:
- Analysis of STAT3 target genes using molecular biology techniques.
- Expression of wild-type and mutant forms of Pim-1 and valosine-containing protein (VCP).
- Assessment of cell proliferation, apoptosis, and gene expression (e.g., bcl-2).
Main Results:
- Pim-1 and Pim-2 were identified as direct targets of the gp130-STAT3 signaling pathway.
- Expression of a kinase-defective Pim-1 mutant inhibited gp130-mediated cell proliferation.
- Constitutive expression of Pim-1 and c-Myc fully restored STAT3-mediated cell cycle progression, anti-apoptosis, and bcl-2 expression.
- Valosine-containing protein (VCP) was identified as a downstream target of Pim-1, and its mutant form induced apoptosis.
Conclusions:
- Pim-family proteins are critical mediators of gp130-STAT3-driven cell proliferation.
- Pim proteins, in conjunction with c-Myc, play a significant role in cell proliferation and lymphomagenesis.
- VCP is a key downstream effector in the Pim-mediated signaling pathway, influencing cell survival.