Abstract
Male germ cell Rac GTPase-activating protein (MgcRacGAP) is a core regulator of cytokinesis. Furthermore, it appears to be involved in human oncogenesis through cytokinesis-independent mechanisms and has been reported to be essential for nuclear translocation of signal transducer and activator of transcription (STAT) proteins, including the oncoprotein STAT3. Here we utilized MgcRacGAP inhibitor compound 1 (MINC1), a small molecule inhibitor of MgcRacGAP, to further investigate how MgcRacGAP regulates STAT3. Surprisingly, both MINC1 treatment and small interference RNA (siRNA)-mediated gene silencing of MgcRacGAP resulted in increased STAT3 phosphorylation and STAT3-driven transcriptional activity in our experimental systems. Finally, we demonstrated that MINC1-induced STAT3 activation likely is due to increased STAT3 phosphorylation caused by a Rac1-PAR3-IL6-IL6R-JAK2 mediated autocrine/paracrine mechanism.
| Original language | English |
|---|---|
| Journal | FEBS Letters |
| Volume | 589 |
| Issue number | 24 Pt B |
| Pages (from-to) | 3859-65 |
| Number of pages | 7 |
| ISSN | 0014-5793 |
| DOIs | |
| Publication status | Published - 21 Dec 2015 |
| Externally published | Yes |
Keywords
- Dose-Response Relationship, Drug
- GTPase-Activating Proteins/antagonists & inhibitors
- Gene Silencing
- HEK293 Cells
- HeLa Cells
- Humans
- Janus Kinase 2/metabolism
- Janus Kinases/metabolism
- Phosphorylation/drug effects
- RNA, Small Interfering/genetics
- Receptors, Interleukin-6/metabolism
- STAT3 Transcription Factor/chemistry
- Signal Transduction/drug effects
- Transcription, Genetic/drug effects
- Tyrosine/metabolism
- rac1 GTP-Binding Protein/metabolism