MCT-1 Oncogene
Synonyms
Definition
MCT-1 is an oncogene initially identified in a human T-cell lymphoma and has been shown to induce cell proliferation as well as activate survival-related pathways. The MCT-1 protein MCT-1 contains a PUA domain, which is a recently described RNA binding domain. MCT-1 interacts with the cap-binding complex and modulates the translation profiles of a subset of mRNAs.
Characteristics
The MCT-1 oncogene is mapped to chromosome Xq22–24. MCT-1 was shown to interact with the density-regulated protein (DENR/DRP), a protein whose expression is increased in cultured cells grown at high density. DENR has a SUI1 domain which is involved in recognition of the initiation codon by the eIF2-GTP-Met-tRNAi ternary complex. Together MCT-1 and DENR form a functional unit which binds to the cap binding complex either directly or indirectly through interaction with eIF4E.
Regulation
Expression analysis of a variety of normal human tissues revealed low-level ubiquitous expression of MCT-1 message. Levels of MCT-1 protein were shown to be increased after exposure to DNA damaging agents; this increase did not require new protein synthesis. Phosphorylation of MCT-1 protein by p44/p42 MAPK is critical for stabilization of MCT-1 protein and for its ability to promote cell proliferation.
Clinical Relevance
A subset of primary diffuse large B-cell lymphomas exhibited significantly elevated levels of MCT-1 protein compared with normal lymphoid tissue. The region of chromosome Xq22–24 has been shown to contain amplified DNA in a variety of primary B-cell lymphoid neoplasms using comparative genomic hybridization, suggesting that increased copy number of a gene(s) located in this region confers a growth advantage. The signaling pathways that regulate the translational machinery are abnormally active in many human cancers and are causally related to tumor formation in mouse models. The MCT-1 protein interacts with the cap-binding complex and modulates mRNA translational profiles through its binding to DENR. Using a comparative genomics approach, a homolog of MCT-1 was identified in the archaeaPyrococcus abyssi. MCT-1 is the only known oncogene homolog in archaea and highlights that MCT-1 is a highly conserved gene with critical biological function. Further underscoring the functional relevance of MCT-1 is the observation that the human MCT-1 gene can complement in yeast the translation defects observed by the loss of the yeast gene TMA20, having significant homology (48%) to MCT-1. It is clear that MCT-1 plays a role in translational regulation, and further supports the linkage between translational control and oncogenesis. Many human malignancies gain a selective advantage through the abnormal activation of this pathway, and its selective inhibition may provide a potential therapeutic approach in malignancies that exhibit high levels of MCT-1 protein.
References
- 1.Prosniak M, Dierov J, Okami K et al (1998) A novel candidate oncogene, MCT-1, is involved in cell cycle progression. Cancer Res 58(19):4233–4237PubMedGoogle Scholar
- 2.Shi B, Hsu HL, Evens AM et al (2003) Expression of the candidate MCT-1 oncogene in B- and T-cell lymphoid malignancies. Blood 102(1):297–302PubMedCrossRefGoogle Scholar
- 3.Sinnathamby L, Nandi S, Helen Hui BS et al (2006) MCT-1protein interacts with the cap complex and modulates mRNA translational profiles. Cancer Res 66(18):8994–9001CrossRefGoogle Scholar
- 4.Nandi S, Reinert LS, Hachem A et al (2006) Phosphorylation of MCT-1 by p42/44 MAPK is required for its stabilization in response to DNA damage. Oncogene [Epub ahead of print]Google Scholar
- 5.Fleischer TC, Weaver CM, McAfee KJ et al (2006) Systematic identification and functional screens of uncharacterized proteins associated with eukaryotic ribosomal complexes. Genes Dev 20(10):1294–1307PubMedPubMedCentralCrossRefGoogle Scholar