| 1998 |
MCTS1 (MCT-1) overexpression decreases cell-doubling time by shortening the G1 phase of the cell cycle without increasing S and G2-M phases, and transforms NIH3T3 fibroblasts (anchorage-independent growth). The protein shares limited amino acid homology with a protein-protein binding domain of cyclin H. |
Overexpression in NIH3T3 cells, cell cycle analysis, soft agar colony formation assay |
Cancer research |
High |
9766643
|
| 1999 |
MCT-1 overexpression in NIH3T3 fibroblasts increases cdk4 and cdk6 kinase activity, elevates cyclin D1 protein levels, and increases G1 cyclin/cdk complex formation, mechanistically linking MCT-1 to deregulation of G1/S checkpoint kinases. |
Kinase activity assays (cdk4, cdk6), Western blotting, co-immunoprecipitation in MCT-1-overexpressing NIH3T3 cells |
Journal of cellular biochemistry |
High |
10440924
|
| 2001 |
MCT-1 protein is stabilized in response to DNA damaging agents (gamma irradiation) without new protein synthesis, indicating post-translational stabilization. MCT-1 is localized to the cytoplasm throughout the cell cycle in human lymphoid tumor cells. |
Western blotting, subcellular fractionation, cell cycle synchronization, protein synthesis inhibition |
Oncogene |
Medium |
11709712
|
| 2005 |
MCT-1 overexpression promotes angiogenesis by dramatically reducing thrombospondin-1 (TSP1) levels in breast cancer xenografts, and inhibits apoptosis. Blocking TSP1 in conditioned medium of MCT-1-negative cells restored angiogenic potential to that of MCT-1-overexpressing cells. |
Xenograft tumor model, microvascular density measurement, conditioned medium rescue experiment, Western blotting |
Cancer research |
Medium |
16322206
|
| 2005 |
MCT-1 overexpression deregulates cell cycle checkpoints: it increases phosphorylation of H2AX and NBS1, increases DNA damage foci, preferentially increases S-phase population after gamma-irradiation, impairs the G1/S checkpoint, and promotes genomic instability. MCT-1 siRNA knockdown attenuates H2AX phosphorylation and the G1/S checkpoint defect. |
siRNA knockdown, gamma-irradiation, flow cytometry, immunofluorescence (gamma-H2AX, 53BP1 foci), transformation assay |
Oncogene |
High |
15897892
|
| 2006 |
MCT-1 protein interacts with the mRNA cap complex through its PUA domain and recruits DENR (DRP), a protein containing the SUI1 translation initiation domain. MCT-1 overexpression modulates the translational profiles of BCL2L2, TFDP1, MRE11A, cyclin D1, and E2F1 mRNAs at the polysome level without altering cytoplasmic mRNA levels. |
Co-immunoprecipitation (cap complex), polysome microarray analysis, PUA domain mutant analysis |
Cancer research |
High |
16982740
|
| 2006 |
Phosphorylation of MCT-1 by p44/p42 MAPK (ERK1/ERK2) is required for MCT-1 protein stabilization and its ability to promote cell proliferation. Genetic and pharmacological inhibition of MEK/ERK reduced MCT-1 phosphorylation and stability. |
Pharmacological MEK inhibitors, dominant-negative ERK, Western blotting for phosphorylated MCT-1, proliferation assays |
Oncogene |
High |
17016429
|
| 2007 |
MCT-1 overexpression decreases p53 expression via ubiquitin-dependent proteasomal degradation (increased ubiquitinated-p53 and phospho-MDM2 levels), and activates MAPK (ERK1/ERK2) phosphorylation. MCT-1 knockdown or MEK/ERK inhibition elevates genotoxin-induced p53 and p21 production. MCT-1 nuclear allocation after genotoxic stress coincides with gamma-H2AX appearance. |
Western blotting, proteasome inhibition rescue, siRNA knockdown, comet assay, spectral karyotyping, immunofluorescence |
DNA repair |
High |
17416211
|
| 2008 |
A PUA-domain mutant of MCT-1 attenuates its oncogenic function: cells expressing the PUA mutant show reduced anchorage-independent growth, increased apoptosis susceptibility, and an altered translational profile, establishing that the PUA domain is essential for MCT-1's translational regulatory activity. |
PUA domain mutagenesis, soft agar assay, apoptosis assay, polysome profiling |
Leukemia research |
Medium |
18824261
|
| 2009 |
ERK phosphorylates MCT-1 and up-regulates it in DLBCL. Pharmacological ERK inhibition disrupts MCT-1 phosphorylation and stability. MCT-1 knockdown by shRNA induces apoptosis in DLBCL cells, demonstrating dependence on MCT-1 for survival. |
shRNA knockdown, ERK small-molecule inhibitor, phosphorylation analysis, xenograft model |
Cancer research |
High |
19789340
|
| 2009 |
MCT-1 accelerates p53 protein degradation via ubiquitin-dependent proteolysis. MCT-1 induction in p53-deficient cells increases chromosomal translocations, deregulates G2-M checkpoint, promotes multinucleation, and activates Ras-MEK-ERK signaling. Loss of p53 and MCT-1 overexpression synergistically promote chromosome instability and tumorigenicity. |
Western blotting, proteasome inhibition, cell cycle analysis, cytogenetics, xenograft model, siRNA |
Molecular cancer research : MCR |
High |
19372582
|
| 2010 |
MCT-1 promoter activity is negatively regulated by wild-type p53 (but not mutant p53) through response elements in the promoter. In a negative feedback loop, MCT-1 suppresses p53 promoter function and p53 mRNA stability. MCT-1 also constitutively stimulates p53 inhibitors MDM2, Pirh2, and COP1. |
Luciferase reporter assays, promoter deletion analysis, mRNA stability assays, Western blotting |
Molecular cancer |
Medium |
21138557
|
| 2012 |
MCT-1 overexpression and PTEN loss synergistically activate Src/p190B signaling, leading to inhibition of RhoA activity, spindle multipolarity, cytokinesis failure, and neoplastic multinucleation. MCT-1 co-immunoprecipitates with p190B and Src in vivo, indicating proximity within a signaling complex. MCT-1 antagonizes PTEN protein stability and functional activity. |
Co-immunoprecipitation, shRNA knockdown, xenograft model, FACS, immunofluorescence |
Oncogene |
High |
24858043
|
| 2012 |
MCT-1 is identified as a centrosomal oncoprotein. Knockdown of MCT-1 causes intercellular bridging, chromosome mis-congregation, cytokinesis delay, and mitotic death. MCT-1 combined with p53 deficiency deregulates mitotic checkpoint kinases, leading to cytokinesis failure, multi-nucleation, centrosome amplification, polyploidy, and aneuploidy. |
siRNA knockdown, immunofluorescence (centrosome staining), cell cycle analysis, long-term cultivation, spindle damage |
Cell cycle |
Medium |
22336915
|
| 2012 |
MCT-1 overexpression activates Shc-Ras-MEK-ERK signaling. MCT-1 knockdown enhances apoptotic cell death with caspase activation. |
shRNA knockdown, Western blotting for Shc/ERK pathway components, apoptosis assay, xenograft model |
Oncotarget |
Medium |
23211466
|
| 2014 |
DENR and MCT-1 (MCTS1) are the first selective regulators of eukaryotic translation re-initiation. mRNAs containing upstream ORFs with strong Kozak sequences selectively require DENR-MCT-1 for their translation. In Drosophila, loss of DENR or MCT-1 reduces tissue growth. |
Drosophila genetics (loss-of-function), reporter assays, ribosome profiling, in vitro translation, polysome analysis |
Nature |
High |
25043021
|
| 2017 |
Crystal structure of the human small ribosomal subunit in complex with DENR-MCT-1 was determined. The C-terminal domain of DENR binds to the 40S subunit at a site strikingly similar to that of canonical eIF1, suggesting that DENR-MCT-1 controls fidelity of translation initiation and re-initiation by mimicking eIF1 function. |
X-ray crystallography of human 40S•DENR-MCT-1 complex |
Cell reports |
High |
28723557
|
| 2017 |
DENR and MCTS1 regulate translation re-initiation on transcripts with short upstream ORFs (stuORFs) in human cells. Only transcripts with very short stuORFs (1 amino acid) are dependent on DENR and MCTS1, identifying ~100 human genes as DENR/MCTS1 translational targets enriched for neuronal genes and GPCRs. |
siRNA knockdown of DENR and MCTS1, polysome profiling, reporter assays in human cells |
Scientific reports |
High |
28623304
|
| 2017 |
MCT-1 overexpression promotes ROS generation, suppresses p53 accumulation, and elevates MnSOD via the YY1-EGFR signaling cascade to protect cells from oxidative damage. Targeting YY1 in lung cancer cells inhibits the EGFR-MnSOD pathway and cell invasiveness induced by MCT-1. |
Western blotting, ROS measurement, siRNA targeting YY1, invasion assay, xenograft model |
Oncogenesis |
Medium |
28394354
|
| 2018 |
Crystal structure of the DENR-MCT-1 heterodimer at 2.0-Å resolution reveals that four conserved DENR cysteines (C34, C37, C44, C53) form a zinc-binding site essential for heterodimer formation; substitution of all four cysteines abolished heterodimer formation. |
X-ray crystallography, site-directed mutagenesis of zinc-coordinating cysteines, co-immunoprecipitation |
Proceedings of the National Academy of Sciences |
High |
30584092
|
| 2018 |
Crystal structure of MCTS1 bound to DENR fragment identifies DENR residues Glu42, Tyr43, Tyr46 as important for MCTS1 binding, and MCTS1 residue Phe104 as important for tRNA binding. DENR-MCTS1 dimerization and tRNA binding are both necessary for the complex to promote translation re-initiation in human cells. DENR-MCTS1 can bind tRNA in the absence of the ribosome, suggesting it recruits tRNA analogously to eIF2. |
X-ray crystallography, site-directed mutagenesis (DENR E42A/Y43A/Y46A; MCTS1 F104A), translation reporter assays in human cells, tRNA binding assay |
PLoS biology |
High |
29889857
|
| 2018 |
Yeast Tma20 (MCT-1) and Tma22 (DENR) function as 40S ribosomal subunit recycling factors in vivo. Ribosome profiling of tma deletion strains revealed 80S ribosomes queued behind stop codons (block in 40S recycling). Unrecycled 40S subunits can reinitiate translation at AUG codons in 3' UTRs, and in vitro translation confirmed increased reinitiation in the absence of these proteins. |
Ribosome profiling (deletion strains), 3' UTR reporter analysis, in vitro translation with uORF reporters |
Molecular cell |
High |
30146315
|
| 2019 |
MCT-1 stimulates IL-6 secretion that promotes monocytic THP-1 polarization into M2-like macrophages, and elevates soluble IL-6 receptor levels. MCT-1 increases breast cancer stem cell features further advanced by IL-6, which are prevented by tocilizumab (IL-6R antibody). Tumor suppressor miR-34a is induced upon MCT-1 knockdown and inhibits IL-6R expression. |
MCT-1 overexpression/knockdown, cytokine ELISA, macrophage polarization assay, sphere formation, miR-34a gain/loss of function |
Molecular cancer |
Medium |
30885232
|
| 2021 |
40S ribosome footprinting directly establishes that yeast Tma20 (MCT-1)/Tma22 (DENR) heterodimer is responsible for the majority of 40S recycling events at stop codons in vivo, while Tma64 (eIF2D) plays a minor role. An autism-associated mutation in TMA22 (DENR) abolishes 40S recycling activity, linking ribosome recycling to neurological disease. |
40S-specific ribosome profiling, gene deletions, autism-associated mutant knock-in |
Nature communications |
High |
34016977
|
| 2023 |
Complete MCTS1 deficiency in humans impairs translation re-initiation of a specific subset of proteins, including JAK2, in all cell types tested (T lymphocytes, phagocytes). Reduced JAK2 expression impairs cellular responses to IL-23 (and partially IL-12), impairing IFN-γ production by MAIT and γδ T cells upon mycobacterial challenge. MCTS1 deficiency is otherwise physiologically redundant. |
Human genetic (X-linked recessive patients), Western blotting/expression of JAK2, cytokine response assays (IL-23, IL-12, IFN-γ), T cell functional assays |
Cell |
High |
37875108
|
| 2020 |
MCTS1 directly binds to TWF1 (twinfilin-1) and this interaction synergistically modulates cyclin D1 and c-Myc translation in luminal A/B breast cancer cells. |
Co-immunoprecipitation, overexpression, Western blotting, translation analysis in BT-474 and MCF-7 cells |
OncoTargets and therapy |
Low |
32606753
|
| 2022 |
MCTS1 interacts with LARP7 in the cytoplasm, increases LARP7 protein half-life, and reduces LARP7 poly-ubiquitination (reducing proteasomal degradation). LARP7 overexpression partially reverses MCTS1 knockdown-induced inhibitory effects on LSCC cell viability. |
Co-IP, cycloheximide chase assay, ubiquitination Co-IP, rescue overexpression, subcellular fractionation |
Clinical and experimental pharmacology & physiology |
Medium |
35274760
|
| 2023 |
MCTS1 interacts with OTUD6B isoform 1 (OTUD6B-1), and this interaction enhances OTUD6B-mediated deubiquitination (cleavage of K48-branched ubiquitin chains) of LIN28B, reducing LIN28B degradation in G1/S cells and promoting cyclin D1, cyclin E1, and c-Myc expression and LSCC cell proliferation. |
Co-IP, ubiquitination assay (K48-branched chains), shRNA knockdown rescue, overexpression, in vitro and in vivo proliferation assays |
Biochemical and biophysical research communications |
Medium |
37634410
|
| 2024 |
MCTS1-DENR-dependent re-initiation is accurately recapitulated in a cell-free (HeLa lysate) in vitro re-initiation assay. MCTS2 (encoded by a retrogene copy of MCTS1) can serve as an alternative DENR partner that promotes re-initiation in vitro. eIF2D knockdown causes widespread gene expression deregulation unrelated to uORF translation, establishing a distinct function from MCTS1-DENR. |
Cell-free re-initiation assay (HeLa lysates), ribosome profiling (siRNA knockdown), reporter assays |
bioRxivpreprint |
Medium |
bio_10.1101_2024.06.05.597545
|
| 2003 |
The MCT-1 promoter is TATA-less with a consensus initiator element and two Sp1 sites directing basal transcription. A region from -133 to -122 contains a positive cis-acting enhancer element that binds a lymphoid-specific nuclear protein (LMBF, ~96 kDa) distinct from known heat shock factors, required for maximal transcriptional activity. |
Luciferase reporter assays, deletion analysis, EMSA, Southwestern blot |
Journal of cellular biochemistry |
Medium |
12938157
|