Abstract
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 RNA-binding 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 polysome-associated 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.
Highlights
The oncogene MCT-1 is amplified in certain human T cell lymphomas and has been mapped to chromosome Xq22-24 [1]
The search for a conserved domain database revealed that DENR contained a SUI1 domain similar to the archetypal translation initiation factor eIF1 (Fig. 1A)
There are several lines of evidence supporting the role of MCT-1 in lymphomagenesis; stimulation of cell proliferation, enhancement of cell survival signaling, enhanced G1 cyclin/cdk kinase activity, elevated levels of MCT-1 protein in primary diffuse large B cell lymphoma, and overriding cell cycle checkpoints
Summary
The oncogene MCT-1 is amplified in certain human T cell lymphomas and has been mapped to chromosome Xq22-24 [1]. This region is amplified in a subset of primary B cell non– Hodgkin 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]. MCT1 contains a PUA domain, a recently described RNA-binding domain that is found in several tRNA and rRNA modification enzymes [9, 10], suggesting that MCT1 might have an RNA-binding function
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