Expression of N-Myristoyltransferase Inhibitor Protein and Its Relationship to c-Src Levels in Human Colon Cancer Cell Lines

Rajala, Raju V S; Dehm, Scott M.; Bi, Xuguang; Bonham, Keith; Sharma, Rajendra K.

doi:10.1006/bbrc.2000.3066

Cited by 26 publications

(21 citation statements)

References 45 publications

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“…NaB and TSA inhibit c-Src mRNA and protein expression Previously we described the overall expression level and relative promoter usage for the SRC gene in a number of human tumor cell lines Dehm et al, 2001;Rajala et al, 2000). For the current study we chose to concentrate on four cell lines, representative of the diversity of c-Src expression we encountered.…”

Section: Resultsmentioning

confidence: 99%

The ubiquitous and tissue specific promoters of the human SRC gene are repressed by inhibitors of histone deacetylases

et al. 2002

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Histone deacetylase inhibitors have generated keen interest as potential chemopreventive and chemotherapeutic agents due to their ability to induce cell cycle arrest, differentiation, and apoptosis in a diverse group of cancer derived cell lines. Activation of the 60 kDa nonreceptor tyrosine kinase, c-Src, has been a consistent finding in many tumors and tumor derived cell lines, and has been implicated in these same cellular processes. We have shown that the histone deacetylase inhibitors, sodium butyrate and Trichostatin A, repressed c-Src mRNA and protein expression in a dose-dependent manner in cell lines derived from cancers of the colon, breast and liver. Our group has previously identified two distinct promoters that are responsible for SRC transcription, separated by a distance of approximately 1 kb. Sodium butyrate and Trichostatin A strongly inhibited activity of each of these highly disparate SRC promoters, demonstrating histone deacetylase inhibitors directly repress SRC transcription. This repression did not require protein neosynthesis and was not associated with a decrease in binding of protein factors essential for either promoter's activity. Our finding that sodium butyrate and Trichostatin A inhibit both SRC promoters suggest this oncogene may be a major target of these agents, and may explain in part their anti-cancer activity.

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Section: Resultsmentioning

confidence: 99%

The ubiquitous and tissue specific promoters of the human SRC gene are repressed by inhibitors of histone deacetylases

et al. 2002

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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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“…We also observed that the NMT expression is elevated in colon (23) and gallbladder carcinoma (24). In addition, we have demonstrated low levels of NMT inhibitor protein (NIP 71 ) in high-expressing c-Src cell lines and high levels of NIP 71 in low-expressing c-Src cell lines (25). Recently, the importance of NMT in cancer has been reviewed (26).…”

Section: Introductionmentioning

confidence: 81%

High Expression of Methionine Aminopeptidase 2 in Human Colorectal Adenocarcinomas

Selvakumar

Lakshmikuttyamma

Kanthan

et al. 2004

Clinical Cancer Research

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Purpose: Several viral and eukaryotic proteins required for signal transduction and regulatory functions undergo lipophilic modification by the enzyme N-myristoyltransferase. Previously we reported that N-myristoyltransferase activity is higher in colon and gallbladder carcinoma than in the corresponding normal tissues. Methionine aminopeptidase 2 (MetAP2) is a bifunctional protein that plays a critical role in the regulation of post-translational processing and protein synthesis. To investigate whether MetAP2 contributes to the pathogenesis of colon carcinoma, we investigated the expression of MetAP2 in both normal and invasive tumor components of human samples.Experimental Design: We evaluated 50 cases of colon carcinoma for this study. In this report we analyzed 15 cases for MetAP2 activity and 13 cases for the expression of MetAP2 by Western blot in both the normal and in invasive tumor components of human samples. In addition, immunohistochemistry analysis was also carried out on samples from all patients.Results: MetAP activity was elevated in all cancerous tissues compared with normal tissues. Western blot analysis also showed the higher expression of MetAP2 in all cases of cancerous tissues. In addition, immunohistochemistry analysis revealed that all cases of colorectal adenocarcinoma showed moderate to strong cytoplasmic positivity for MetAP2 with increased intensity in the invasive component. Conclusions:Elevated MetAP protein expression is associated with metastatic tumor progression and appears to be a strong molecular marker for clinical prognosis. MetAP2 inhibition may represent a potential target for therapeutic intervention in colorectal carcinoma.

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Expression of N-Myristoyltransferase Inhibitor Protein and Its Relationship to c-Src Levels in Human Colon Cancer Cell Lines

Cited by 26 publications

References 45 publications

The ubiquitous and tissue specific promoters of the human SRC gene are repressed by inhibitors of histone deacetylases

The ubiquitous and tissue specific promoters of the human SRC gene are repressed by inhibitors of histone deacetylases

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

High Expression of Methionine Aminopeptidase 2 in Human Colorectal Adenocarcinomas

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