MORT (Mortal Obligate RNA Transcript (also known as ZNF667-AS1)) is a long non-coding RNA (lncRNA) of the intergenic type (lincRNA) that is specific for humans and great apes.[2] The MORT transcript is produced in mortal cell types, but it is absent in a large fraction of immortalized human cells and cancer cells and therefore might have a tumor suppressive function.
Genomic location
The MORT gene is located on human chromosome 19, at position 56,989,000-57,007,000 (hg19) inside a cluster of zinc finger genes (ZNF genes). The MORT gene consists of 2 exons, 260 and 1270 bp, respectively, separated by a 16 kbp intron. The promoter of MORT gene is part of a CpG island. Upstream of the MORT promoter, but within the same CpG island, is the promoter of the ZNF667 gene. Despite the MORT gene's location inside a cluster of ZNF genes, the MORT gene is not homologous to any ZNF genes. A large portion of the second MORT exon is formed by repetitive elements – two LINEs and an LTR element.[2] Although the MORT gene is located in a head to head orientation relative to ZNF667, MORT does not overlap theZNF667 gene, nor does it share any antisense homology to ZNF667, so the officially used symbol ZNF667-AS1 is somewhat misleading.
Evolution
MORT has orthologs only in great apes – chimpanzees, gorillas and orangutans, and the RNA expression data indicates that the MORT transcript is present in these species.[2] Thus, from the phylogenetic point view, MORT is likely a young lincRNA gene that emerged during evolution of great apes. It is possible that the long life span of the great apes needed evolution of additional genes with tumor suppressive activity, and that MORT is an example of such.
Silencing in cancer
MORT is expressed in all 16 normal human tissues reported on in the Illumina body map data,[3] as well as all in vitro cultured, finite lifespan, human cell strains analyzed by 2015. In contrast, MORT gene expression is lost in a large percentage of human cancers and human cancer cell lines. Using data from human cancers curated in TCGA, MORT RNA expression and DNA methylation state were evaluated in the 10 most common male cancers and the 10 most common female cancers[4] (totalling 17 different cancer types based on TCGA classification). Analysis shows that MORT gene expression is silenced and the MORT gene promoter is hypermethylated in a majority of tumor samples in 15 of these 17 human cancers.[2]
The 15 tumor types where MORT is frequently silenced are acute myeloid leukemia, bladder urothelial carcinoma, breast invasive carcinoma, colon adenocarcinoma, head and neck squamous-cell carcinoma, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, pancreatic adenocarcinoma, rectum adenocarcinoma, skin cutaneous melanoma, and Uterine Corpus Endometrial Carcinoma.[2]
Using a novel model of human mammary epithelial cell immortalization, it was found that the MORT gene is epigenetically silenced at the mortal/immortal boundary[2] where mortal, finite lifespan cells pathologically transform into immortal cells with limitless replicative potential.[5] Since immortality is an essential feature acquired by human tumor cells, MORT may play a tumor suppressive role in human carcinogenesis, and its inactivation creates a cellular state permissive to immortalization. The precise molecular function of MORT remains enigmatic; however, it is known that MORT is found preferentially in the cell cytoplasm with differential density centrifugation indicating that MORT is enriched in the 100,000 g fraction, which contains polysomes, microsomes, endoplasmic reticulum, and the plasma membrane.[6]
References
- ↑ "Human PubMed Reference:".
- 1 2 3 4 5 6 Vrba L, Garbe JC, Stampfer MR, Futscher BW (2015). "A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers". Epigenetics. 10 (11): 1074–83. doi:10.1080/15592294.2015.1106673. PMID 26646903.
- ↑ "MORT expression in Illumina Body Map Data".
- ↑ "Cancer Facts & Figures" (PDF). Atlanta: American Cancer Society. 2015.
- ↑ Garbe JC, Vrba L, Sputova K, Fuchs L, Novak P, Brothman AR, Jackson M, Chin K, LaBarge MA, Watts G, Futscher BW, Stampfer MR (2014). "Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations". Cell Cycle. 13 (21): 3423–35. doi:10.4161/15384101.2014.954456. PMID 25485586.
- ↑ Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J (2000). Molecular Cell Biology (4th ed.). New York: W. H. Freeman. ISBN 978-0-7167-3136-8.