This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Petersen Shay, K. Articles by Magnuson, N. S. Search for Related Content PubMed PubMed Citation Articles by Petersen Shay, K. Articles by Magnuson, N. S.

---

Signaling and Regulation

Pim-1 Kinase Stability Is Regulated by Heat Shock Proteins and the Ubiquitin-Proteasome Pathway

¹ School of Molecular Biosciences, Washington State University, Pullman, Washington and ² Austin Research Institute, Heidelberg, Victoria, Australia

Requests for reprints: Nancy S. Magnuson, School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4234. Phone: 509-335-0966; Fax: 509-335-1907. E-mail: magnuson{at}wsu.edu

Elevated expression of the serine/threonine kinase Pim-1 increases the incidence of lymphomas in Pim-1 transgenic mice and has also been found to occur in some human cancers. Pim-1 acts as a cell survival factor and may prevent apoptosis in malignant cells. It was therefore of interest to understand to what extent maintenance and degradation of Pim-1 protein is affected by heat shock proteins (Hsp) and the ubiquitin-proteasome pathway in K562 and BV173 human leukemic cells. The half-life of Pim-1 protein in these cells was found to increase from 1.7 to 3.1 hours when induced by heat shock or by treating the cells with the proteasome inhibitor PS-341 (bortezomib). The Hsp90 inhibitor geldanamycin prevented the stabilization of Pim-1 by heat shock. Using immunoprecipitation, it was determined that Pim-1 is targeted for degradation by ubiquitin and that Hsp70 is associated with Pim-1 under these circumstances. Conversely, Hsp90 was found to protect Pim-1 from proteasomal degradation. A luminescence-based kinase assay showed that Pim-1 kinase bound to Hsp70 or Hsp90 remains active, emphasizing the importance of its overall cellular levels. This study shows how Pim-1 levels can be modulated in cells through degradation and stabilization.

Key Words: Pim-1 • serine/threonine kinase • Hsp70 • Hsp90 • ubiquitin • 26S proteasome • heat shock • geldanamycin • PS-341

This article has been cited by other articles:

				M. Zemskova, E. Sahakian, S. Bashkirova, and M. Lilly The PIM1 Kinase Is a Critical Component of a Survival Pathway Activated by Docetaxel and Promotes Survival of Docetaxel-treated Prostate Cancer Cells J. Biol. Chem., July 25, 2008; 283(30): 20635 - 20644. [Abstract] [Full Text] [PDF]

				V. Pogacic, A. N. Bullock, O. Fedorov, P. Filippakopoulos, C. Gasser, A. Biondi, S. Meyer-Monard, S. Knapp, and J. Schwaller Structural Analysis Identifies Imidazo[1,2-b]Pyridazines as PIM Kinase Inhibitors with In vitro Antileukemic Activity Cancer Res., July 15, 2007; 67(14): 6916 - 6924. [Abstract] [Full Text] [PDF]