This Article 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 Rizzo, M. T. Articles by Weber, G. Search for Related Content PubMed PubMed Citation Articles by Rizzo, M. T. Articles by Weber, G.

1-Phosphatidylinositol 4-Kinase: An Enzyme Linked with Proliferation and Malignancy¹

Laboratory for Experimental Oncology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202-5200

The activity of 1-phosphatidylinositol 4-kinase (EC 2.7.1.67), the first committed ATP-utilizing enzyme of inositol 1,4,5-trisphosphate and diacylglycerol biosynthesis, was determined in a spectrum of rat hepatomas of different growth rates, in sarcoma, and in normal tissues of high cell renewal rates which include differentiating and regenerating liver. A standard isotopic method was developed to measure the enzymic activity in crude particulate extracts. In this assay, the enzyme activity was linear with time for 2 min and proportional with protein concentrations over a range of 0.1 to 1.0 mg per 0.1 ml reaction mixture. The optimum pH for both liver and hepatoma enzyme was 7.4. The apparent K_m values of the kinase for ATP, Mg²⁺, and the substrate phosphatidylinositol in normal liver were 0.03, 10, and 0.2 mM, respectively, and in rapidly growing hepatoma 3924A 0.01, 0.1, and 5.3 mM. The kinase activity in adult rat livers was 0.3 to 0.5 ± 0.01 nmol/h/mg protein. In hepatomas of slow and intermediate growth rates, kinase activity increased 5.3- to 7.6-fold, and in rapidly proliferating hepatoma 3924A, it was elevated 28.5-fold over that of normal liver. In rat sarcoma, kinase activity was 13.2-fold higher than in normal muscle. To clarify further the linkage between kinase activity and proliferation, enzymic activity was determined in rapidly growing rat tissues. The kinase activity in rat thymus, bone marrow, spleen, and testis increased 8.4-, 7.6-, 5.6- and 5.6-fold, respectively, over the values of normal rat liver; by contrast, in skeletal muscle, liver, heart, and renal cortex, the activities were low. In the rapidly growing neonatal rat liver and in 24-h regenerating liver, activities were 3.4- and 3.0-fold higher than in the adult resting liver.

From this study, the relationship of 1-phosphatidylinositol 4-kinase activity with transformation and cell proliferation is clearly apparent in the markedly increased activity in transplantable hepatomas of different growth rates and in sarcoma and is further emphasized by the high activity observed in newborn and regenerating liver and in thymus, bone marrow, spleen, and testis. Since the kinase activity is linked with proliferation and malignancy, it may well be a sensitive target for chemotherapy.

¹ This work was supported in part by USPHS Outstanding Investigator Grant CA-42510 awarded to G. W.

² Present address: Division of Hematology and Bone Marrow Transplantation, Parma University, Via Gramsci 14, Parma 43100, Italy.

³ To whom requests for reprints should be addressed, at Laboratory for Experimental Oncology, Indiana University School of Medicine, 702 Barnhill Drive, Indianapolis, IN 46202-5200.

Received 1/13/94. Accepted 3/21/94.

This article has been cited by other articles:

				R. Das, G. H. Mahabeleshwar, and G. C. Kundu Osteopontin Stimulates Cell Motility and Nuclear Factor {kappa}B-mediated Secretion of Urokinase Type Plasminogen Activator through Phosphatidylinositol 3-Kinase/Akt Signaling Pathways in Breast Cancer Cells J. Biol. Chem., August 1, 2003; 278(31): 28593 - 28606. [Abstract] [Full Text] [PDF]

				G. H. Mahabeleshwar and G. C. Kundu Syk, a Protein-tyrosine Kinase, Suppresses the Cell Motility and Nuclear Factor kappa B-mediated Secretion of Urokinase Type Plasminogen Activator by Inhibiting the Phosphatidylinositol 3'-Kinase Activity in Breast Cancer Cells J. Biol. Chem., February 14, 2003; 278(8): 6209 - 6221. [Abstract] [Full Text] [PDF]

				D. Sliva, M. T. Rizzo, and D. English Phosphatidylinositol 3-Kinase and NF-kappa B Regulate Motility of Invasive MDA-MB-231 Human Breast Cancer Cells by the Secretion of Urokinase-type Plasminogen Activator J. Biol. Chem., January 25, 2002; 277(5): 3150 - 3157. [Abstract] [Full Text] [PDF]