Increased G1 cyclin/cdk activity in cells overexpressing the candidate oncogene,MCT-1

Dierov, Jamil; Prosniak, Misha; Gallia, Gary L.; Gartenhaus, Ronald B.

doi:10.1002/(sici)1097-4644(19990915)74:4<544::aid-jcb4>3.0.co;2-4

Cited by 27 publications

(23 citation statements)

References 16 publications

(16 reference statements)

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“…MCT-1 was previously shown to play a role in cell cycle progression, apoptosis, and DNA damage response (5)(6)(7)(8)34). In order to identify if the increased translation of genes participating in these processes was caused by the up-regulation of MCT-1, we isolated polysomal RNA fractions as previously described from 293HEK cells transiently transfected with V5-MCT-1 or vector control plasmids.…”

Section: Resultsmentioning

confidence: 99%

“…This region is amplified in a subset of primary B cell nonHodgkin lymphomas, suggesting that increased copy number of a gene(s) located in this region confers a growth advantage to certain primary human lymphomas (2)(3)(4). Lymphoma cell lines overexpressing MCT-1 exhibited increased growth rates and displayed increased protection against serum starvation-induced apoptosis when compared with matched controls (1,5,6). Recently, we showed that MCT-1 impairs cell cycle checkpoint control after exposure to DNA-damaging agents and transforms human mammary epithelial cells (7).…”

Section: Introductionmentioning

confidence: 97%

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MCT-1 Protein Interacts with the Cap Complex and Modulates Messenger RNA Translational Profiles

et al. 2006

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MCT-1 is an oncogene that was initially identified in a human T cell lymphoma and has been shown to induce cell proliferation as well as activate survival-related pathways. MCT-1 contains the PUA domain, a recently described RNAbinding domain that is found in several tRNA and rRNA modification enzymes. Here, we established that MCT-1 protein interacts with the cap complex through its PUA domain and recruits the density-regulated protein (DENR/ DRP), containing the SUI1 translation initiation domain. Through the use of microarray analysis on polysomeassociated mRNAs, we showed that up-regulation of MCT-1 was able to modulate the translation profiles of BCL2L2, TFDP1, MRE11A, cyclin D1, and E2F1 mRNAs, despite equivalent levels of mRNAs in the cytoplasm. Our data establish a role for MCT-1 in translational regulation, and support a linkage between translational control and oncogenesis. (Cancer Res 2006; 66(18): 8994-9001)

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

MCT-1 Protein Interacts with the Cap Complex and Modulates Messenger RNA Translational Profiles

et al. 2006

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“…Overexpression of MCT-1 leads to increased cell proliferation, a shortened G1 phase, increased cyclin D1 expression, and an ability to grow in soft agar (Prosniak et al 1998;Dierov et al 1999). Recent data link MCT-1 with the DNA damage checkpoint and angiogenesis (Hsu et al 2005;Levenson et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Systematic identification and functional screens of uncharacterized proteins associated with eukaryotic ribosomal complexes

Fleischer¹,

Weaver²,

McAfee³

et al. 2006

Genes Dev.

262

266

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Translation regulation is a critical means by which cells control growth, division, and apoptosis. To gain further insight into translation and related processes, we performed multifaceted mass spectrometry-based proteomic screens of yeast ribosomal complexes and discovered an association of 77 uncharacterized yeast proteins with ribosomes. Immunoblotting revealed an EDTA-dependent cosedimentation with ribosomes in sucrose gradients for 11 candidate translation-machinery-associated (TMA) proteins. Tandem affinity purification linked one candidate, LSM12, to the RNA processing proteins PBP1 and PBP4. A second candidate, TMA46, interacted with RBG1, a GTPase that interacts with ribosomes. By adapting translation assays to high-throughput screening methods, we showed that null yeast strains harboring deletions for several of the TMA genes had alterations in protein synthesis rates (TMA7 and TMA19), susceptibility to drugs that inhibit translation (TMA7), translation fidelity (TMA20), and polyribosome profiles (TMA7, TMA19, and TMA20). TMA20 has significant sequence homology with the oncogene MCT-1. Expression of human MCT-1 in the ⌬tma20 yeast mutant complemented translation-related defects, strongly implying that MCT-1 functions in translation-related processes. Together these findings implicate the TMA proteins and, potentially, their human homologs, in translation related processes.[Keywords: Mass spectrometry; proteomics; ribosome; Saccharomyces cerevisiae; translation] Supplemental material is available at http://www.genesdev.org.

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“…15,36,37 Furthermore, several studies from our group have shown that an oncogene directly downstream of MEK/ERK, MCT-1, is involved in cell proliferation, suppression of apoptosis, enhancement of cell survival signaling, and enhanced G1 cyclin/CDK kinase activity. 8,9,[38][39][40] Previous work from our group showed in a large-scale immunohistochemical (IHC) screen that MCT-1 protein was strongly expressed in 85% of DLBCL samples (weak and strong expression Ͼ 95%) compared with only 6% of follicular lymphoma cases. 15 Moreover, we showed that genetic knockdown of MCT-1 resulted in apoptosis and tumor regression.…”

Section: Discussionmentioning

confidence: 99%

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

Bhalla

Evens

Dai

et al. 2011

Blood

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IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults accounting for nearly 35% of all non-Hodgkin lymphomas (NHL). Significant advances have been in the treatment of DLBCL, particularly with immunochemotherapy, however approximately 30%-40% of patients still die from this malignancy. In addition, short-and long-term toxicities of chemotherapy, including secondary malignancies and leukemias, continue to adversely impact the long-term prognosis of patients. Continued investigations of novel targeted therapeutic agents in DLBCL are warranted.The RAS/RAF/mitogen-activated protein kinase 1/2 (MEK1/2)/ extracellular signal-regulated kinase 1/2 (ERK1/2) plays a prominent role in cancer biology, including hematologic malignancies, in part through the regulation of cell growth and proliferation. [1][2][3][4][5] Activating mutations in RAS and RAF lead to aberrant activation of their downstream target, MEK1/2. Directly downstream of MEK1/2, ERK1 and ERK2 are intimately involved in transducing signals from growth factor receptors and cytokine receptors after ligand binding. 2 Furthermore, ERK is the only known catalytic substrate of MEK. 6 We and others have shown that the MEK/ERK signaling pathway is constitutively active in a large number of cancers, including hematologic malignancies. 3,4,[7][8][9] Moreover, the MEK/ERK signal transduction cascade has been shown to be susceptible to pharmacologic intervention. Thus, MEK has emerged as an attractive therapeutic target in cancer.The majority of preclinical, and especially clinical trial data studying MEK inhibitors to date have emerged largely from solid tumor studies. [10][11][12][13][14] We recently showed in preclinical studies that inhibition of ERK1/2 phosphorylation by 1st generation MEK and ERK inhibitors correlated with significant cell death in a lymphoma tumor model, 15 while others showed that sublethal concentrations of a 1st generation MEK antagonist potentiated the effect of sorafemib in lymphoma cells. 16 Furthermore, we recently demonstrated that MCT-1, an oncogene directly downstream of MEK/ ERK, is over-expressed in the majority of primary DLBCLs. 15 MCT-1 is known to colocalize with ERK1/2, while phosphorylation of MCT-1 protein by ERK is critical for stabilization of MCT-1 protein and for its functional ability to promote cell proliferation. 15,17 ARRY-142886 (AZD6244, selumetinib; Astra Zeneca) is a selective nonATP-competitive 2nd generation oral MEK inhibitor studied primarily in solid tumor studies with reported nanomolar activity against purified MEK1 enzyme. [18][19][20][21][22][23] Furthermore, phase 1 and phase 2 solid tumor clinical trials have shown this agent to be well-tolerated and have encouraging clinical efficacy. [24][25][26][27] To our knowledge, minimal data are available on newer generation MEK inhibitors in lymphoma and moreover, this anti-MEK agent has never been examined in lymphoma. We sought to examine the mechanisms of action and cytotoxic effect of the novel 2nd generation MEK sma...

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Increased G1 cyclin/cdk activity in cells overexpressing the candidate oncogene,MCT-1

Cited by 27 publications

References 16 publications

MCT-1 Protein Interacts with the Cap Complex and Modulates Messenger RNA Translational Profiles

MCT-1 Protein Interacts with the Cap Complex and Modulates Messenger RNA Translational Profiles

Systematic identification and functional screens of uncharacterized proteins associated with eukaryotic ribosomal complexes

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

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