Synergistic Roles for Pim-1 and c-Myc in STAT3-Mediated Cell Cycle Progression and Antiapoptosis

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.

Celecoxib induces apoptosis and cell-cycle arrest in nasopharyngeal carcinoma cell lines via inhibition of STAT3 phosphorylation

“…Constitutive STAT3 activation has a critical role in tumor development and tumorigenesis in multiple tumors and cell lines. Critical gene expression changes induced by aberrant activation of STAT3 may promote cancer cell growth and survival via the upregulation of Cyclin D1, c-Myc, Pim-1 [26,27] . Additionally, STAT3 may inhibit apoptosis via the upregulation of Bcl-2, Survivin and Mcl-1 [28][29][30] .…”

Negative regulation of Pim-1 protein kinase levels by the B56β subunit of PP2A

“…Figure 8b demonstrates (Qian et al, 2005b). It is interesting that Pim-1 has been shown to transform cells in concert with both c-Myc (Verbeek et al, 1991;Shirogane et al, 1999;Ellwood-Yen et al, 2003) or Akt (Amaravadi and Thompson, 2005), and that the levels of both of these proteins are regulated by PP2A (Sears, 2004;Ugi et al, 2004;Van Kanegan et al, 2005). Using a model in which hematopoietic cells are grown in an IL-3-dependent fashion, we find that knocking down a PP2A B subunit increases viability only in Pim containing, but not in Pim knockout cells.…”

Genome-wide analysis of STAT target genes: Elucidating the mechanism of STAT-mediated oncogenesis

“…45 The genes that mediate the proliferative effects of STATs include the D and E type cyclins, the cdk inhibitor p21, and the transcription factor c-myc. 19,28,42,[46][47][48][49] The pro-angiogenic effects of STAT3 are likely to be mediated through upregulation of VEGF. 34,35 STAT3 regulation of matrix metalloproteinase-2 (mmp-2) correlates with invasiveness of melanoma cells, 38 and activation of mmp-9 is required for STAT3-induced transformation of mammary epithelial cells.…”