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Stat3 plays an important role in oncogenic Ros- and insulin-like growth factor I receptor-induced
1Departments of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA. zongc01@doc.mssm.edu
Abstract:
The role of signal transducers and activators of transcription (STATs) in receptor protein-tyrosine kinase (PTK)-induced cell growth and transformation was investigated using an inducible epidermal growth factor receptor-Ros chimeric receptor called ER2 and a constitutively activated insulin-like growth factor I receptor called NM1, both of which are able to induce anchorage-independent growth of NIH 3T3 cells. ER2 and NM1 receptor PTKs are able to cause Stat3 activation. Co-expressing the dominant negative Stat3 mutant with ER2 or NM1 in transiently or stable transfected cells resulted in a dramatic inhibition of colonies induced by these receptor PTKs and a moderate inhibition of their mitogenicity in monolayer. Therefore, Stat3 is not only important for initiation of transformation, as demonstrated by inhibition of the epidermal growth factor-inducible colony formation of the ER2 cells by the mutant, but it is also required for the maintenance of transformation, as evidenced by reversion of the NM1 transformed cells. The DNA binding and transcriptional activities of the endogenous Stat3 were greatly inhibited in the ER2 and NM1 cells co-expressing the Stat3 mutants. We conclude that activated function of Stat3 is required for the establishment and maintenance of Ros and insulin-like growth factor I receptor PTK-induced cell transformation.
Insights
Signal transducers and activators of transcription (STATs), specifically Stat3, are crucial for initiating and maintaining cell transformation induced by receptor protein-tyrosine kinases (PTKs). Inhibiting Stat3 function dramatically reduces anchorage-independent growth and reverts transformed cells.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Receptor protein-tyrosine kinases (PTKs) play a key role in regulating cell growth and transformation.
- Signal transducers and activators of transcription (STATs) are critical signaling molecules involved in cellular processes.
Purpose of the Study:
- To investigate the role of STATs, particularly Stat3, in PTK-induced cell growth and transformation.
- To determine if Stat3 is required for both the initiation and maintenance of transformation.
Main Methods:
- Utilized inducible ER2 (chimeric epidermal growth factor receptor-Ros) and constitutively activated NM1 (insulin-like growth factor I receptor) PTKs in NIH 3T3 cells.
- Employed dominant-negative Stat3 mutants in transient and stable transfections to assess Stat3 function.
- Measured colony formation (anchorage-independent growth) and mitogenicity (monolayer growth).
Main Results:
- ER2 and NM1 receptor PTKs activate Stat3.
- Co-expression of dominant-negative Stat3 mutants significantly inhibited colony formation induced by ER2 and NM1.
- Moderate inhibition of mitogenicity was observed with Stat3 mutant co-expression.
- Stat3 mutant expression inhibited endogenous Stat3 DNA binding and transcriptional activity.
- Stat3 is essential for both initiating and maintaining transformation.
Conclusions:
- Activated Stat3 function is essential for the establishment and maintenance of cell transformation induced by Ros and insulin-like growth factor I receptor PTKs.
- Targeting Stat3 may offer therapeutic strategies for PTK-driven cancers.