Depletion of Methionine Aminopeptidase 2 Does Not Alter Cell Response to Fumagillin or Bengamides

Kim, Sunkyu; LaMontagne, Kenneth R.; Sabio, Michael; Sharma, Sushil; Versace, Richard; Yusuff, Naeem; Phillips, Penny E.

doi:10.1158/0008-5472.can-04-0019

Cited by 53 publications

(50 citation statements)

References 14 publications

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“…Recently, Kim et al (2004) has proposed that human MAP2 is not the target for the antiangiogenic effect of fumagillin, suggesting that the drug could also target other important cellular molecules in animal epithelial cells. With the plant system, we found that fumagillin has no effect on wild-type and Cmap2 KD lines.…”

Section: Map2s Versus Map1s: Overlapping or Redundant Functions In Himentioning

confidence: 99%

Functional and Developmental Impact of Cytosolic Protein N-Terminal Methionine Excision in Arabidopsis

et al. 2005

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Protein N-terminal methionine (Met) excision (NME) is carried out by two types of Met aminopeptidases (MAPs), MAP1 and MAP2, in eukaryotes. Three enzymes, MAP1A, MAP2A, and MAP2B, have been identified in the cytoplasm of Arabidopsis (Arabidopsis thaliana). MAP transcript quantification revealed a predominance of MAP2B and developmental and organ-specific regulation of both MAP1A and MAP2s. By combining reverse genetics and reverse chemogenomics in transgenic plant lines, we have devised specific and reversible switches for the investigation of the role of cytoplasmic NME in Arabidopsis and of the respective contributions of the two types of cytoplasmic MAPs throughout development. dsRNA interference and knockout (KO) plant lines targeting either MAP1A alone or both MAP2s simultaneously were constructed and shown to display wild-type phenotypes. In the MAP1A KO context, modulating MAP2 activity by treatment with various concentrations of the specific drug fumagillin impaired plant development, with particularly strong effects on the root system. Reciprocally, complete MAP2 inhibition in various MAP1A knocked-down genetic backgrounds also generated a gradient of developmentally abnormal plants, but the effects on the root system were milder than in the KO context. In the absence of MAP2 activity, the severity of the phenotype in the MAP1A knocked-down lines was correlated to the extent of MAP1A mRNA accumulation. Complete cytoplasmic NME inactivation blocked development after plant germination. Thus, in plants, (1) cytoplasmic NME is essential; (2) MAP1A and MAP2s are functionally interchangeable, which is not the case in fungi and animals, as a complete block of either MAP-type activity does not cause any visible molecular or phenotypic effect; and (3) a minimal level of cytoplasmic MAP is required for normal development.

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Section: Map2s Versus Map1s: Overlapping or Redundant Functions In Himentioning

confidence: 99%

Functional and Developmental Impact of Cytosolic Protein N-Terminal Methionine Excision in Arabidopsis

et al. 2005

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“…MetAP2 expression is up-regulated in various human cancers, including mesothelioma, 40 B-cell lymphomas, 41 colorectal adenocarcinoma, 42 neurofibromatosis 1-associated human astrocytic tumor, 43 as well as cholangiocarcinoma, 44 and modulation of MetAP2 activity could present a target for therapeutic intervention. [45][46][47] The zebrafish model offers a unique opportunity in which the effects of metap2 modulation on hematopoietic and endothelial cells can be simultaneously examined and its high-throughput nature can enable pharmacologic screening for the rapid identification of therapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

Methionine aminopeptidase 2 is required for HSC initiation and proliferation

Alvin¹,

Fung²,

Lin³

et al. 2011

Blood

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In a chemical screening, we tested the antiangiogenic effects of fumagillin derivatives and identified fumagillin as an inhibitor of definitive hematopoiesis in zebrafish embryos. Fumagillin is known to target methionine aminopeptidase II (MetAP2), an enzyme whose function in hematopoiesis is unknown. We investigated the role of MetAP2 in hematopoiesis by using zebrafish embryo and human umbilical cord blood models. Zebrafish metap2 was expressed ubiquitously during early embryogenesis and later in the somitic region, the caudal hematopoietic tissue, and pronephric duct. metap2 was inhibited by morpholino and fumagillin treatment, resulting in increased mpo expression at 18 hours postfertilization and reduced c-myb expression along the ventral wall of dorsal aorta at 36 hours postfertilization. It also disrupted intersegmental vessels in Tg-(fli1:gfp) embryos without affecting development of major axial vasculatures. Inhibition of MetAP2 in CB CD34 ؉ cells by fumagillin had no effect on overall clonogenic activity but significantly reduced their engraftment into immunodeficient nonobese diabetes/severe combined immunodeficiency mice.

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“…In fact, the primary mouse embryonic fibroblasts were demonstrated to be sensitive to TNP470 and other MetAP2-specific inhibitors in a p53-dependent fashion. Several MetAP2 inhibitors were studied based on the inhibition of MetAP activity (Griffith et al, 1998;Antoine et al, 1994;Kusaka et al, 1994;Wang et al, 2000;Wang et al, 2003;Yeh et al, 2000;Zhang et al, 2000;Kim et al, 2004;Towbin et al, 2003).…”

Section: Notementioning

confidence: 99%

“…TNP470 entered human clinical trials for the treatment of AIDS-related Kaposi's sarcoma, metastatic breast cancer, androgen-independent prostate cancer, pediatric solid tumors, lymphomas, acute leukemia, advanced squamous cell cancer of the cervix, and metastatic renal carcinoma (Dezube et al, 1998;Kruger and Figg, 2000;Kudelka et al, 1997). Several MetAP2 inhibitors were studied based on the inhibition of MetAP activity (Griffith et al, 1998;Antoine et al, 1994;Kusaka et al, 1994;Wang et al, 2000;Yeh et al, 2000;Zhang et al, 2000;Kim et al, 2004). Previously, inhibition of MetAP2 by TNP470 has been shown to activate p53 for cell-cycle arrest (Yeh et al, 2000;Zhang et al, 2000).…”

Section: Metap2 Inhibitorsmentioning

confidence: 99%