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Murine embryonic fibroblasts lacking TC-PTP display delayed G1 phase through defective NF-κB activation

Oncogene volume 20, pages 4728–4739 (2001)Cite this article

Abstract

Previous results suggested a potential role for T-cell protein tyrosine phosphatase (TC-PTP) in cell proliferation. However, no conclusive data has supported such a function in the modulation of this process. In order to clarify this issue, we isolated TC-PTP−/− murine embryonic fibroblasts (MEFs) as well as cell lines to characterize the role of TC-PTP in the control of cell proliferation and cell cycle. Both TC-PTP−/− primary MEFs and cell lines proliferate slower than TC-PTP+/+ cells. We also demonstrated that TC-PTP−/− cells have a slow progression through the G1 phase of the cell cycle. Further characterization of the G1 defect indicates that the kinetics of cyclin D1 induction was delayed and that p27KIP1 remains at higher levels for an extended period of time. Moreover, cells lacking TC-PTP showed a delayed activation of CDK2. This slow progression through the early G1-phase resulted in decreased phosphorylation of the RB protein and subsequent delay into the S phase transition. In contrast, no further defects were detected in other phases of the cell cycle. Survey of the potential signaling pathways leading to this delayed cyclin D1 expression indicated that NF-κB activation was compromised and that IKKβ activity was also reduced following PDGF stimulation. Reintroduction of wild-type TC-PTP into the TC-PTP−/− cells rescued the defective proliferation, cyclin D1 expression, NF-κB activation as well as IκB phosphorylation. Together, these results confirm that TC-PTP plays a positive role in the progression of early G1 phase of the cell cycle through the NF-κB pathway.

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Acknowledgements

We are grateful to Phil E Branton for the generous gift of anti-RB antibody. We thank Alan Cheng, Jean François Côté, Mounib Elchebly, Pankaj Tailor and François Blondeau for helpful discussion and critical reading of the manuscript. We acknowledge the contribution of Eva Michaliszyn, Jacklin Quinlan and Ailsa Lee Loy for their excellent technical work. We also thank Louie Lamorte and Morag Park for their suggestions and help in the generation of the TC-PTP retrovirus expression vector. María de Jesús Ibarra-Sánchez received studentships from the Canderel Foundation, the Alexander McFee Memorial Fellowship and the Internal Studentship of Faculty of Medicine at McGill University. ML Tremblay is a Scientist of Canadian Institutes for Health Research (CIHR). This work was supported by an operating grant to ML Tremblay from the National Cancer Institute (NCI) of Canada.

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Authors and Affiliations

  1. McGill Cancer Centre and Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, H3G 1Y6, Quebec, Canada

    María de Jesús Ibarra-Sánchez, John Wagner, Ming-Thong Ong, Carmen Lampron & Michel L Tremblay

  2. Kinetek Pharmaceuticals Inc. Vancouver, British Columbia, V6P 6G5, Canada

    John Wagner, Ming-Thong Ong & Carmen Lampron

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  1. María de Jesús Ibarra-Sánchez
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Correspondence to Michel L Tremblay.

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Ibarra-Sánchez, M., Wagner, J., Ong, MT. et al. Murine embryonic fibroblasts lacking TC-PTP display delayed G1 phase through defective NF-κB activation. Oncogene 20, 4728–4739 (2001). https://doi.org/10.1038/sj.onc.1204648

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