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Nuclear Transport of Parathyroid Hormone (PTH)-Related Protein Is Dependent on Microtubules

Nuclear Signaling Laboratory, Division of Biochemistry and Molecular Biology (M.H.C.L., D.A.J.), John Curtin School of Medical Research, Canberra, ACT 2601; Department of Biochemistry and Molecular Biology (M.H.C.L., D.A.J.), Monash University, Clayton, Victoria 3168; St. Vincent’s Institute of Medical Research (R.J.T., T.J.M, M.T.G.), Fitzroy, Victoria 3065; Institute of Reproduction and Development (K.L.L.), Monash Medical Centre, Clayton, Victoria 3168; Centre for Micro-Photonics (S.S., M.G.), School of Biophysical Sciences and Electrical Engineering, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia

Address all correspondence and requests for reprints to: Professor D. A. Jans, c/o Nuclear Signaling Laboratory, Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, GPO Box 334, Canberra, ACT 2601, Australia. E-mail: David. Jans{at}med.monash.edu.au

PTH-related protein (PTHrP) was first discovered as a circulating factor secreted by certain cancers and is responsible for the syndrome of humoral hypercalcemia of malignancy induced by various tumors. The similarity of its N terminus to that of PTH enables PTHrP to share the signaling properties of PTH, but the rest of the molecule possesses distinct functions, including a role in the nucleus/nucleolus in reducing apoptosis and enhancing cell proliferation. PTHrP nuclear import is mediated by importin ß1. In this study we use the technique of fluorescence recovery after photobleaching to demonstrate the ability of PTHrP to shuttle between cytoplasm and nucleus and to visualize directly the transport of PTHrP into the nucleus in living cells. Endogenous and transfected PTHrP was demonstrated to colocalize with microtubule structures in situ using various high-resolution microscopic approaches, as well as in in vitro binding studies, where importin ß1, but not importin , enhanced the microtubular association of PTHrP with microtubules. Significantly, the dependence of PTHrP nuclear import on microtubules was shown by the inhibitory effect of pretreatment with the microtubule-disrupting agent nocodazole on nuclear-cytoplasmic flux. These results indicate that PTHrP nuclear/nucleolar import is dependent on microtubule integrity and are consistent with a direct role for the cytoskeleton in protein transport to the nucleus.

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