| Expression | - MTUS1 isoform 1 and 2 are the major MTUS1 transcripts in all tissues except brain
- MTUS1 isoform 3 is absent (or weakly expressed) in all normal tissues examined
- MTUS1 isoform 4 is exclusively expressed in the brain, and is particularly abundant in the cerebellum and in the fetal brain. |
| Localisation | MTUS1 isoform 5 is the only isoform localized in mitochondria. |
| Function | The MTUS1 isoform 5 was the first one among the 5 different isoforms to be characterized independently in 2 laboratories, as a gene that is transiently upregulated during initiation of differentiation and quiescence in a 3-dimensional human umbilical vein endothelial cell culture, and as a early component of growth inhibitory signaling cascade that interacts with angiotensin II AT2 receptor. The exon 8, which is exclusively utilized by MTUS1 isoform 5, contains a mitochondrial targeting signal. This protein isoform has indeed been shown to co-localize with mitochondria, which eventually lead to its current name mitochondrial tumor suppressor 1. These early evidences on MTUS1 isoform 5 suggest the tumor suppressor function of this gene. As a consequence, the majority of the functional analyses have been focused on this specific isoform. As demonstrated in a pancreatic tumor cell line (MIA PaCa-2), recombinant expression of MTUS1 isoform 5 led to a 30% reduction in cell growth as measured by BrdU uptake. Using a CHO cell line stably transfected with both angiotensin II AT2 receptor and MTUS1 isoform 5, Nouet et al. demonstrated that the growth factors (insulin, bFGF, EGF) induced extracellular regulated kinase ( ERK2 ) activation was inhibited. This MTUS1 isoform 5 mediated inhibitory effect was also observed at cell proliferation level as measured by DNA synthesis. The results from Nouet et al., 2006 study also suggested that MTUS1 isoform 5 functions through cooperating with the angiotensin II AT2 receptor to trans-inactivate growth factor receptor tyrosine kinases. The localization of the MTUS1 isoform 5 to mitochondria also lead to speculation that this protein achieves its tumor suppressor function by regulating different mitochondrial functions, such as the maintenance of energy supply, the production of reactive oxygen intermediates and their interactions with other cell cycle regulators.
While ample evidence suggested the tumor suppressor function of isoform 5, it is important to notice that isoform 1 and 2 are the major MTUS1 transcripts in all tissues except brain, and account for an average of 72% of total MTUS1 mRNA. Evidence supporting the tumor suppressor function of MTUS1 isoform 1 and 2 come from the study on Xenopus Icis gene, a homolog of MTUS1 isoform 1/2. Using inactivating antibodies, Ohi et al. found that absence of Icis caused excessive microtubule growth and inhibited spindle formation, a function consistent with tumor suppressor activity. Prior to anaphase, Icis localized to inner centromeres in a Mitotic Centromere Associated Kinesin ( Mcak )-dependent manner. From Xenopus extracts, Icis coimmunoprecipitated Mcak and the inner centromere proteins Incenp and AuroraB, which are thought to promote chromosome biorientation. Immunoelectron microscopy detected Icis on the surface of inner centromeres, in an ideal location to depolymerize microtubules associated laterally with inner centromeres. Ohi et al. hypothesized that Mcak-Icis may destabilize these microtubules and provide a mechanism that prevents kinetochore-microtubule attachment errors.
The MTUS1 isoform 1 and isoform 2 differ in their use of exon 4; exon 4 is contained in isoform 1 but not in isoform 2 (Figure 2). This difference may be a result of alternative splicing. Alternatively, this isoform 2 may be a protein product from the MTUS1 gene with a recently identified polymorphic copy number variant at DNA level (Var del Ex4 that lacking the exon 4).
The existence of MTUS1 isoform 3 is not entirely certain. The expression of MTUS1 isoform 3 appears to be under the control of the same gene promoter that drives the expression of the isoform 1 and 2. However, as a result of alternative splicing, exon 3, which contains an in-frame stop codon, is incorporated into the transcript. This sequence feature makes the transcript variant 3 a candidate for nonsense-mediated mRNA decay (NMD). Indeed, it is absent (or weakly expressed) in all normal tissues examined. Hence, the sequence for this variant in the GenBank (NM_001001927) was permanently suppressed. Nevertheless, it is possible that this alternative splice to include exon 3 in the transcript may provide a mechanism to switch-off the expression of isoform 1 and 2 at posttranscriptional level.
The MTUS1 isoform 4 is exclusively expressed in the brain, and is particularly abundant in the cerebellum and in the fetal brain. It appears that the expression of isoform 4 is driven by a gene promoter specific to central nervous system. These findings suggest multiple cellular/physiological functions of MTUS1 gene, including tumor suppression as well as brain function and/or development. |
| Homology | Xenopus Icis gene is a homolog of MTUS1 isoform 1 and 2. |
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