This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nguyen, M. T. A. Articles by Karaplis, A. C. Search for Related Content PubMed PubMed Citation Articles by Nguyen, M. T. A. Articles by Karaplis, A. C.

Nuclear Forms of Parathyroid Hormone-Related Peptide Are Translated from Non-AUG Start Sites Downstream from the Initiator Methionine¹

Division of Endocrinology, Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital and Lady Davis Institute for Medical Research, McGill University, Montréal, Canada H3T 1E2

Address all correspondence and requests for reprints to: Andrew C. Karaplis, Lady Davis Institute for Medical Research, 3755 Côte-Ste-Catherine Road, Montréal, Québec, Canada, H3T 1E2. E-mail: akarapli{at}ldi.jgh.mcgill.ca

PTH-related peptide (PTHrP), normally a secreted protein, exerts at least part of its biological functions via intracrine actions at the level of the cell nucleus/nucleolus. To gain insight into the mechanism whereby this peptide accesses the cytosol for subsequent nuclear import, we characterized its nuclear forms. In transfected COS-1 cells, three nuclear PTHrP species were produced, which were larger than the mature form of the protein but smaller than prepro-PTHrP and comprised both the amino- and carboxyl-terminal regions of the peptide. This suggested that nuclear PTHrP proteins contain part of the prepropeptide and likely arise from alternate initiation of translation at downstream non-AUG codons within the signal sequence. Transient expression of two PTHrP forms, one in which the unique initiator ATG was mutated to a noninitiator ATC codon, and another encompassing an engineered N-linked glycosylation site, generated peptides of size comparable to nuclear PTHrP proteins. These were inefficiently targeted to the ER, bypassed ER transit, and exclusively localized to nucleoli. Using a polyclonal antiserum against the pro-region of PTHrP, nuclear PTHrP species were shown to harbor the propeptide sequence. Hence, our data argue that nuclear PTHrP forms result from translation initiated at alternate, internal codons. This may constitute the first example of translation initiation at downstream non-AUG codons in a mammalian protein.

This article has been cited by other articles:

				N. Fiaschi-Taesch, B. M. Sicari, K. Ubriani, T. Bigatel, K. K. Takane, I. Cozar-Castellano, A. Bisello, B. Law, and A. F. Stewart Cellular Mechanism Through Which Parathyroid Hormone-Related Protein Induces Proliferation in Arterial Smooth Muscle Cells: Definition of an Arterial Smooth Muscle PTHrP/p27kip1 Pathway Circ. Res., October 27, 2006; 99(9): 933 - 942. [Abstract] [Full Text] [PDF]

				N. Bhattacharyya, K. Pechhold, H. Shahjee, G. Zappala, C. Elbi, B. Raaka, M. Wiench, J. Hong, and M. M. Rechler Nonsecreted Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Can Induce Apoptosis in Human Prostate Cancer Cells by IGF-independent Mechanisms without Being Concentrated in the Nucleus J. Biol. Chem., August 25, 2006; 281(34): 24588 - 24601. [Abstract] [Full Text] [PDF]

				N. Fiaschi-Taesch, K. K. Takane, S. Masters, J. C. Lopez-Talavera, and A. F. Stewart Parathyroid Hormone-Related Protein as a Regulator of pRb and the Cell Cycle in Arterial Smooth Muscle Circulation, July 13, 2004; 110(2): 177 - 185. [Abstract] [Full Text] [PDF]

				N. M. Fiaschi-Taesch and A. F. Stewart Minireview: Parathyroid Hormone-Related Protein as an Intracrine Factor--Trafficking Mechanisms and Functional Consequences Endocrinology, February 1, 2003; 144(2): 407 - 411. [Abstract] [Full Text] [PDF]

				F. de Miguel, N. Fiaschi-Taesch, J. C. Lopez-Talavera, K. K. Takane, T. Massfelder, J.-J. Helwig, and A. F. Stewart The C-Terminal Region of PTHrP, in Addition to the Nuclear Localization Signal, Is Essential for the Intracrine Stimulation of Proliferation in Vascular Smooth Muscle Cells Endocrinology, September 1, 2001; 142(9): 4096 - 4105. [Abstract] [Full Text] [PDF]

				M. M. Aarts, D. Davidson, A. Corluka, E. Petroulakis, J. Guo, F. R. Bringhurst, J. Galipeau, and J. E. Henderson Parathyroid Hormone-related Protein Promotes Quiescence and Survival of Serum-deprived Chondrocytes by Inhibiting rRNA Synthesis J. Biol. Chem., October 5, 2001; 276(41): 37934 - 37943. [Abstract] [Full Text] [PDF]