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

Previous results suggested a potential role for T-cell protein tyrosine pho sphatase (TC-PTP) in cell proliferation. However, no conclusive data has su pported such a function in the modulation of this process. In order to clar ify this issue, we isolated TC-PTP-/- murine embryonic fibroblasts (MEFs) a s well as cell lines to characterize the role of TC-PTP in the control of c ell proliferation and cell cycle. Both TC-PTP-/- primary MEFs and cell line s 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. F urther characterization of the G1 defect indicates that the kinetics of cyc lin D1 induction was delayed and that p27(KIP1) remains at higher levels fo r an extended period of time. Moreover, cells lacking TC-PTP showed a delay ed activation of CDK2. This slow progression through the early G1-phase res ulted in decreased phosphorylation of the RB protein and subsequent delay i nto the S phase transition. In contrast, no further defects were detected i n other phases of the cell cycle. Survey of the potential signaling pathway s leading to this delayed cyclin D1 expression indicated that NF-kappaB act ivation was compromised and that IKK beta activity was also reduced followi ng PDGF stimulation. Reintroduction of wild-type TC-PTP into the TC-PTP-/- cells rescued the defective proliferation, cyclin D1 expression, NF-kappaB, activation as well as I kappaB phosphorylation. Together, these results co nfirm that TC-PTP plays a positive role in the progression of early G1 phas e of the cell cycle through the NF-kappaB pathway.