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Requirement of N-Myristoyltransferase 1 in the Development of Monocytic Lineage¹

Anuraag Shrivastav^*,, Shailly Varma, Zoe Lawman, Shao H. Yang, Shawn A. Ritchie, Keith Bonham, Sukh M. Singh^¶, Anurag Saxena^* and Rajendra K. Sharma^2,*,

^* Department of Pathology and Department of Biochemistry, College of Medicine, University of Saskatchewan, and Health Research Division, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada; Department of Medicine, University of California, Los Angeles, CA 90095; and ^¶ School of Biotechnology, Faculty of Science, Banaras Hindu University, Varanasi, India

N-myristoyltransferase (NMT) exists in two isoforms, NMT1 and NMT2, that catalyze myristoylation of various proteins crucial in signal transduction, cellular transformation, and oncogenesis. We have recently demonstrated that NMT1 is essential for the early development of mouse embryo. In this report, we have demonstrated that an invariant consequence of NMT1 knock out is defective myelopoesis. Suppressed macrophage colony forming units were observed in M-CSF-stimulated bone marrow cells from heterozygous (+/–) Nmt1-deficient mice. Homozygous (–/–) Nmt1-deficient mouse embryonic stem cells resulted in drastic reduction of macrophages when stimulated to differentiate by M-CSF. Furthermore, to understand the requirement of NMT1 in the monocytic differentiation we investigated the role of NMT, pp60^c–Src (NMT substrate) and heat shock cognate protein 70 (inhibitor of NMT), during PMA-induced differentiation of U937 cells. Src kinase activity and protein expression increased during the differentiation process along with regulation of NMT activity by hsc70. NMT1 knock down in PMA treated U937 cells showed defective monocytic differentiation. We report in this study novel observation that regulated total NMT activity and NMT1 is essential for proper monocytic differentiation of the mouse bone marrow cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from Canadian Institutes for Health Research (to R.K.S.) and partially supported by a grant from Canadian Institutes for Health Research (to K.B.). A.S. holds a postdoctoral fellowship from Canadian Institutes of Health Research and Saskatchewan Health Research Foundation.

² Address correspondence and reprint requests to Dr. Rajendra K. Sharma, 20 Campus Drive, Saskatoon, Saskatchewan, Canada S7N 4H4. E-mail address: rajendra.sharma{at}saskcancer.ca

³ Abbreviations used in this paper: NMT, N-myristoyltransferase; NIP71, N-myristoyltransferase inhibitor protein 71; hsc70, heat shock cognate protein 70; ES, embryonic stem cell; WT, wild type; siRNA, small interfering RNA; BMDM, bone marrow derived macrophages; BMC, bone marrow cell; mMCSF, mouse M-CSF.