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Decreased cyclin-dependent kinase activity promotes thyroid hormone-dependent tail regression in Rana catesbeiana

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Abstract

The thyroid hormone (TH), 3,5,3′-triiodothyronine (T3), is an important regulator of diverse cellular processes including cell proliferation, differentiation, and apoptosis, with increasing evidence that the modulation of the phosphoproteome is an important factor in the TH-mediated response. However, little is understood regarding the mechanisms whereby phosphorylation may contribute to T3-mediated cellular outcomes during development. The cyclin-dependent kinases (Cdks) and mitogen-activated protein kinases (MAPK/ERK) have been implicated in TH signaling in mammalian cells. In this study, we have investigated, in frogs, the possible role that these kinases may have in the promotion of tail regression during tadpole metamorphosis, an important postembryonic process that is completely TH-dependent. Cdk2 steady state levels and activity increase in the tail concurrent with progression through the growth phase of metamorphosis, followed by a precipitous decrease coinciding with tail regression. Cyclin-A-associated kinase activity also follows a similar trend except that its associated kinase activity is maintained longer before a decrease in activity. Protein steady state levels of ERK1 and ERK2 remain relatively constant, and their kinase activities do not decrease until much later during tail regression. Tail tips cultured in serum-free medium in the presence of T3 undergo regression, which is accelerated by coincubation with a specific Cdk2 inhibitor. Coincubation with PD098059, a MAPK inhibitor, has no effect. Thus, T3-dependent tail regression does not require MAPKs, but a decrease in Cdk2 activity promotes tail regression.

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Acknowledgments

We thank D. Domanski for expert technical support and Dr. N. Veldhoen, D. Domanski, M.J. Wagner, C. Bailey, L. Ji, and Dr. F. Zhang for helpful discussions and critical reading of the manuscript. We are grateful to T. Hunt at the Imperial Cancer Research Fund, UK, for providing the cyclin A2 antibody. C.C.H. would like to acknowledge Dr. K.Y. Lee, University of Calgary, for his kinase assay expertise in the early stages of this investigation.

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Correspondence to Caren C. Helbing.

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This work was supported by a NSERC operating grant, NSERC University Faculty Award, and Michael Smith Foundationfor Health Research Scholar Award.

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Skirrow, R.C., Helbing, C.C. Decreased cyclin-dependent kinase activity promotes thyroid hormone-dependent tail regression in Rana catesbeiana . Cell Tissue Res 328, 281–289 (2007). https://doi.org/10.1007/s00441-006-0362-6

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