Expression of N-myristoyltransferase in Human Brain Tumors

Lu, Yanjie; Selvakumar, Ponniah; Ali, K.; Shrivastav, Anuraag; Bajaj, Gagan; Resch, Lothar; Griebel, Robert; Fourney, Daryl R.; Meguro, Kotoo; Sharma, Rajendra K.

doi:10.1007/s11064-004-9680-9

Cited by 38 publications

(26 citation statements)

References 30 publications

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“…In human ovarian adenocarcinoma cells, siRNA mediated suppression of Nmt2 expression resulted in a 19-fold increase in apoptosis (Ducker et al, 2005). In addition, the gene has been shown to be inducible by various types of carcinogens such as dioxin (Kolluri et al, 2001) and elevated levels of Nmt2 expression have been described in multiple tumor tissues (Lu et al, 2005; Selvakumar and Sharma, 2007). These data, albeit all generated in malignant cells and tissues, suggest an anti-apoptotic function of the up-regulated expression.…”

Section: Discussionmentioning

confidence: 99%

Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo

Meurers¹,

Zhu²,

Fernagut³

et al. 2009

Neurobiology of Disease

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Mitochondrial complex I inhibition has been implicated in the degeneration of midbrain dopaminergic (DA) neurons in Parkinson’s disease. However, the mechanisms and pathways that determine the cellular fate of DA neurons downstream of the mitochondrial dysfunction have not been fully identified. We conducted cell-type specific gene array experiments with nigral DA neurons from rats treated with the complex I inhibitor, rotenone, at a dose that does not induce cell death. The genome wide screen identified transcriptional changes in multiple cell death related pathways that are indicative of a simultaneous activation of both degenerative and protective mechanisms. Quantitative PCR analyses of a subset of these genes in different neuronal populations of the basal ganglia revealed that some of the changes are specific for DA neurons, suggesting that these neurons are highly sensitive to rotenone. Our data provide insight into potentially defensive strategies of DA neurons against disease relevant insults.

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Section: Discussionmentioning

confidence: 99%

Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo

Meurers¹,

Zhu²,

Fernagut³

et al. 2009

Neurobiology of Disease

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“…Over-expression also occurs relatively early in carcinogenesis, in colonic polyps that are not yet malignant [119]. There is also evidence for the overexpression of NMT in gallbladder and oral squamous cell carcinomas [121,122] and brain tumours [123]. Clegg and co-workers have looked at NMT in mammary epithelial cells and found that proliferative capacity correlated with NMT activity [124].…”

Section: Nmt In Cancermentioning

confidence: 99%

Protein myristoylation in health and disease

et al. 2009

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N-myristoylation is the attachment of a 14-carbon fatty acid, myristate, onto the N-terminal glycine residue of target proteins, catalysed by N-myristoyltransferase (NMT), a ubiquitous and essential enzyme in eukaryotes. Many of the target proteins of NMT are crucial components of signalling pathways, and myristoylation typically promotes membrane binding that is essential for proper protein localisation or biological function. NMT is a validated therapeutic target in opportunistic infections of humans by fungi or parasitic protozoa. Additionally, NMT is implicated in carcinogenesis, particularly colon cancer, where there is evidence for its upregulation in the early stages of tumour formation. However, the study of myristoylation in all organisms has until recently been hindered by a lack of techniques for detection and identification of myristoylated proteins. Here we introduce the chemistry and biology of N-myristoylation and NMT, and discuss new developments in chemical proteomic technologies that are meeting the challenge of studying this important co-translational modification in living systems.Keywords Post-translational modification . Drug design . Myristoylation . Lipidation . Chemical proteomics Post-translational modification and myristoylationThe proteome is a larger and more dynamic entity than the genome, a result of both increased sequence diversity at the mRNA level due to alternative splicing of genes, and increased chemical and functional complexity at the protein level due to post-translational modification (PTM). This explains to some extent why larger genomes do not necessarily translate into more complex organisms. Posttranslational modification allows the incorporation of chemistries and new molecular functions that cannot be directly encoded by the gene sequence. Myristoylation is the attachment of a 14-carbon saturated fatty acid, myristate, to the N-terminal glycine of a subset of eukaryotic proteins [8,16,17]. Although often referred to as a PTM, it usually occurs co-translationally [18], when fewer than 100 residues have been polymerised by the

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“…Recently, it has been shown that the enzyme myristoylCoA:protein N-myristoyltransferase (NMT) that is involved in the post-translational modification of c-Src is also overexpressed in colon tumor cells and human brain tumors (13)(14)(15)(16)(17). Further, inhibiting the myristoylation of Src in colon cancer cell lines prevents the localization of the kinase to the plasma membrane and results in decreased colony formation and cell proliferation (18).…”

Section: Introductionmentioning

confidence: 99%

Two N-Myristoyltransferase Isozymes Play Unique Roles in Protein Myristoylation, Proliferation, and Apoptosis

Ducker

Upson

French

et al. 2005

Molecular Cancer Research

104

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N-myristoyltransferases (NMT) add myristate to the NH 2 termini of certain proteins, thereby regulating their localization and/or biological function. Using RNA interference, this study functionally characterizes the two NMT isozymes in human cells. Unique small interfering RNAs (siRNA) for each isozyme were designed and shown to decrease NMT1 or NMT2 protein levels by at least 90%. Ablation of NMT1 inhibited cell replication associated with a loss of activation of c-Src and its target FAK as well as reduction of signaling through the c-Raf/mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway. Terminal deoxynucleotidyl transferase -mediated dUTP nick end labeling assays showed that depletion of either NMT isozyme induced apoptosis, with NMT2 having a 2.5-fold greater effect than NMT1. Western blot analyses revealed that loss of NMT2 shifted the expression of the BCL family of proteins toward apoptosis. Finally, intratumoral injection of siRNA for NMT1 or for both NMT1 and NMT2 inhibited tumor growth in vivo, whereas the same treatment with siRNA for NMT2 or negative control siRNA did not. Overall, the data indicate that NMT1 and NMT2 have only partially overlapping functions and that NMT1 is critical for tumor cell proliferation.

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Expression of N-myristoyltransferase in Human Brain Tumors

Cited by 38 publications

References 30 publications

Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo

Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo

Protein myristoylation in health and disease

Two N-Myristoyltransferase Isozymes Play Unique Roles in Protein Myristoylation, Proliferation, and Apoptosis

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