Unexpected Transcriptional Signals in Normal and Mitotically Defective Cells Mediated Through Cytokine and Growth Factor Receptors

Polypeptide growth factors and cytokines mediate their biochemical functions through their responsive receptors. Known cytokine receptors do not possess intrinsic kinase domains whereas several polypeptide growth factor receptors do. Nevertheless, both classes of ligands are capable of activating sets of overlapping genes. In human epidermoid carcinoma cells, for example, both cytokines and epidermal growth factor (EGF) promote a common transcriptional activation signal through the tyrosine phosphorylation of stat91 (signal transducer and activator of transcription) proteins. The stat family of cytoplasmic proteins also appear to have dual functions. Tyrosine phosphorylated 'stats' are employed for signal transduction and, second, for activation of transcription of several genes. The transcription factor-SIE-DNA binding patterns are now known to be different for EGF and interferon-γ IFN-γ-treated cells. Nevertheless, in the active DNA-bound complex, the stat91 polypeptide is a component found in either EGF or INF-γ-treated extracts. Other stat family members of transcription factors may also be present in the complexes. In this case, tyrosine phosphorylated stat91 polypeptides may form into homodimeric or heterodimeric assemblies with other stat-related transcription factors. We describe a novel stat-related factor, p93, that is found in EGF-treated A431 cell extracts but appears to be absent in bovine fibroblast growth factor (bFGF), IFN-γ, tumor necrosis factor-α (TNF-α), and untreated cells. p93 appears to be antigenically related to stat91.

p185^c-neu+, EGFr⁺ (M1), and p185^c-neu− kinase inactive, EGFr⁺ (NEN757) expressing cells undergo different mitotic responses to EGF. M1 can respond to EGF mitotically while NEN757 cannot. Both cell lines respond to 10 ng/ml of EGF and also to IFN-γ in transducing transcriptional activation signals to the nucleus, despite the distinct growth response to EGF. Our work has analyzed the stat pathway in these types of cells and found similar patterns of usage despite the distinct EGF-responsive features. Cytoplasmic nonreceptor tyrosine kinases Jak1 and Jak2 may be involved in the activation of stat91 and other transcription factors in EGF and IFN-γ signaling pathways. Collectively, these studies suggest that the major EGF-stimulated mitotic growth pathways may not be absolutely linked to the stat91 signaling pathways and that such transcription complexes are more complex than previously reported.