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Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Oncogene volume 19, pages 924–932 (2000)Cite this article

Abstract

Hormones are specialized mitogens that stimulate proliferation in their differentiated target cells. Thyrotropin (TSH), the physiologic regulator of thyroid cells, stimulates cAMP-mediated proliferation and thyroid-specific gene expression. The mitogenic effects of TSH require Ras, therefore Ras activation should be compatible with the maintenance of thyroid differentiation. However, expression of activated Ras extinguishes the differentiated phenotype of thyroid cells. One explanation for this apparent paradox is the selective utilization of Ras effector pathways. We tested the hypothesis that Ras signaling through PI3K mediates the mitogenic effects of TSH in cells which retain their differentiated character. Expression of a Ras effector mutant (RasV12S35) that signals preferentially through Raf-1, although sufficient to confer TSH-independent proliferation, abolished hormone-regulated expression of thyroglobulin and the sodium/iodide symporter. In contrast, expression of a Ras mutant (RasV12C40) that binds selectively to PI3K conferred TSH-independent proliferation without marked effects on thyroid-specific gene expression. Unlike the inhibitory effects of TSH on the proliferation of RasV12S35-expressing cells, TSH enhanced RasV12C40-stimulated proliferation by further increasing the activity of p70s6k, an important mediator of the mitogenic effects of TSH and RasV12C40. These results demonstrate that channeling Ras-dependent signals to PI3K confers TSH with the ability to stimulate proliferation in differentiated cells.

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Acknowledgements

We thank Dr M White for providing the V12RasC40 and V12RasS35 mutants, Drs N Carrasco, M Birnbaum, J Olefsky, J Fox and V Lee for providing NIS and phospho-S6 antibodies, GST-p85-N-SH2, AdlacZ and AdN17Ras, respectively. We acknowledge Greg Prendergast for expert technical support. This work was supported by PHS grants DK45696 and DK02494 to JL Meinkoth.

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  1. Department of Pharmacology, University of Pennsylvania School of Medicine, 36th Street and Hamilton Walk, Philadelphia, PA 19104-6084, Pennsylvania, USA

    Lisa A Cass & Judy L Meinkoth

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Cass, L., Meinkoth, J. Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation. Oncogene 19, 924–932 (2000). https://doi.org/10.1038/sj.onc.1203393

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