MORT (long non-coding RNA): Difference between revisions
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== Genomic location == | == Genomic location == | ||
The ''MORT'' gene is located on [[Chromosome 19 (human)|human chromosome 19]], at position 56,989,000-57,007,000 ([[UCSC Genome Browser|hg19]]) | The ''MORT'' gene is located on [[Chromosome 19 (human)|human chromosome 19]], at position 56,989,000-57,007,000 ([[UCSC Genome Browser|hg19]]) within a cluster of zinc finger genes (ZNF genes). The ''MORT'' gene consists of 2 [[exon]]s, 260 and 1270 bp, respectively, that are separated by a 16 kbp [[intron]]. A large portion of the second ''MORT'' exon is formed by repetitive elements – two LINEs and an LTR element.<ref name="Vrba_2015" /> | ||
The ''MORT'' [[Promoter (genetics)|promoter]] is located in a [[CpG site#CpG islands|CpG island]] | The ''MORT'' [[Promoter (genetics)|promoter]] is located in a [[CpG site#CpG islands|CpG island]] that is shared with the ''ZNF667'' gene; the two genes reside in a head to head orientation with one another. Despite the ''MORT'' gene's location inside a cluster of ZNF genes, the ''MORT'' gene is not homologous to any ZNF genes. While the ''MORT'' gene is in a head to head orientation with ''ZNF667'', ''MORT'' does not overlap the ''ZNF667'' gene, nor does it share any antisense homology to ''ZNF667'', so the officially used symbol ''ZNF667-AS1'' is somewhat misleading. | ||
== Evolution == | == Evolution == | ||
''MORT'' has orthologs only in [[Hominidae|great apes]] – chimpanzees, gorillas and orangutans, and the RNA expression data indicates that the ''MORT'' transcript is | ''MORT'' has orthologs only in [[Hominidae|great apes]] – chimpanzees, gorillas and orangutans, and the RNA expression data indicates that the ''MORT'' transcript is expressed in these species.<ref name="Vrba_2015" /> Thus, from a 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 required evolution of additional genes with tumor suppressive activity, and that ''MORT'' is such an example. | ||
== Silencing in cancer == | == Silencing in cancer == | ||
''MORT'' is expressed in all 16 normal human tissues reported in the [[Illumina (company)|Illumina]] body map data,<ref>{{cite web | title = MORT expression in Illumina Body Map Data | url = https://www.ebi.ac.uk/gxa/experiments/E-MTAB-513?accessKey=&serializedFilterFactors=&queryFactorType=ORGANISM_PART&rootContext=&heatmapMatrixSize=50&displayLevels=false&displayGeneDistribution=false&geneQuery=%5B%7B%22value%22%3A%22ZNF667-AS1%22%7D%5D&_queryFactorValues=1&specific=true&_specific=on&cutoff=0.5}}</ref> as well as all ''in vitro'' cultured, finite lifespan, human cell strains that have been analyzed. 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 [[The Cancer Genome Atlas|TCGA]], ''MORT'' RNA expression and [[DNA methylation]] state were evaluated in the 10 most common male cancers and the 10 most common female cancers<ref>{{cite web | publisher = American Cancer Society | year = 2015 | title = Cancer Facts & Figures | location = Atlanta | url = http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf }}</ref> (totalling 17 different cancer types based on TCGA classification). Analysis shows that the ''MORT'' gene expression is silenced by DNA hypermethylation of its CpG island promoter in a majority of human tumor samples in 15 of these 17 human cancers.<ref name="Vrba_2015" /> | ''MORT'' is expressed in all 16 normal human tissues reported in the [[Illumina (company)|Illumina]] body map data,<ref>{{cite web | title = MORT expression in Illumina Body Map Data | url = https://www.ebi.ac.uk/gxa/experiments/E-MTAB-513?accessKey=&serializedFilterFactors=&queryFactorType=ORGANISM_PART&rootContext=&heatmapMatrixSize=50&displayLevels=false&displayGeneDistribution=false&geneQuery=%5B%7B%22value%22%3A%22ZNF667-AS1%22%7D%5D&_queryFactorValues=1&specific=true&_specific=on&cutoff=0.5}}</ref> as well as all ''in vitro'' cultured, finite lifespan, human cell strains that have been analyzed. 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 [[The Cancer Genome Atlas|TCGA]], ''MORT'' RNA expression and [[DNA methylation]] state were evaluated in the 10 most common male cancers and the 10 most common female cancers<ref>{{cite web | publisher = American Cancer Society | year = 2015 | title = Cancer Facts & Figures | location = Atlanta | url = http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf }}</ref> (totalling 17 different cancer types based on TCGA classification). Analysis shows that the ''MORT'' gene expression is silenced by DNA hypermethylation of its CpG island promoter in a majority of human tumor samples in 15 of these 17 human cancers.<ref name="Vrba_2015" /> | ||
The 15 tumor types where ''MORT'' is frequently silenced are [[acute myeloid leukemia]], [[Bladder cancer|bladder urothelial carcinoma]], [[Breast cancer|breast invasive carcinoma]], [[Colorectal cancer|colon adenocarcinoma]], [[head and neck squamous-cell carcinoma]], [[Kidney cancer|kidney renal clear cell carcinoma]], [[Kidney cancer|kidney renal papillary cell carcinoma]], [[Hepatocellular carcinoma|liver hepatocellular carcinoma]], [[lung adenocarcinoma]], [[Squamous-cell carcinoma of the lung|lung squamous cell carcinoma]], [[Diffuse large B-cell lymphoma|lymphoid neoplasm diffuse large B-cell lymphoma]], [[pancreatic adenocarcinoma]], [[Colorectal cancer|rectum adenocarcinoma]], [[Melanoma|skin cutaneous melanoma]], and [[Uterine cancer|Uterine Corpus Endometrial Carcinoma]].<ref name="Vrba_2015" /> | The 15 tumor types where ''MORT'' is frequently silenced are [[acute myeloid leukemia]], [[Bladder cancer|bladder urothelial carcinoma]], [[Breast cancer|breast invasive carcinoma]], [[Colorectal cancer|colon adenocarcinoma]], [[head and neck squamous-cell carcinoma]], [[Kidney cancer|kidney renal clear cell carcinoma]], [[Kidney cancer|kidney renal papillary cell carcinoma]], [[Hepatocellular carcinoma|liver hepatocellular carcinoma]], [[lung adenocarcinoma]], [[Squamous-cell carcinoma of the lung|lung squamous cell carcinoma]], [[Diffuse large B-cell lymphoma|lymphoid neoplasm diffuse large B-cell lymphoma]], [[pancreatic adenocarcinoma]], [[Colorectal cancer|rectum adenocarcinoma]], [[Melanoma|skin cutaneous melanoma]], and [[Uterine cancer|Uterine Corpus Endometrial Carcinoma]].<ref name="Vrba_2015" /> MORT is silenced in cervical cancer and therefore may serve as an independent [[prognostic factor]] with low MORT expression be associated with a decreased overall survival.<ref name="pmid29243775">{{cite journal | vauthors = Zhao LP, Li RH, Han DM, Zhang XQ, Nian GX, Wu MX, Feng Y, Zhang L, Sun ZG | title = Independent prognostic Factor of low-expressed LncRNA ZNF667-AS1 for cervical cancer and inhibitory function on the proliferation of cervical cancer | journal = European Review for Medical and Pharmacological Sciences | volume = 21 | issue = 23 | pages = 5353–5360 | year = 2017 | pmid = 29243775 | doi = 10.26355/eurrev_201712_13920 }}</ref> | ||
Since cell immortality is an obligate feature of the cancer cell and ''MORT'' was discovered as a target of epigenetic silencing at the boundary where finite lifespan human cells transition from mortal to immortal, ''MORT’s'' epigenetic inactivation may create a cellular state permissive to cell immortalization and suggests a possible tumor suppressive mechanism of ''MORT''’s action. If this prediction is true, then epigenetic silencing of ''MORT'' should be an early identifiable lesion during human carcinogenesis and predicted to occur in premalignant lesions where cells have acquired pathologic immortality on their route to malignant transformation. Indeed, recent work has shown that ''MORT'' is epigenetically silenced in both [[Ductal carcinoma in situ|DCIS]], a premalignant lesion of invasive breast cancer, and colonic adenomas, a premalignant lesion of colon adenocarcinoma.<ref name="Vrba_2017">{{cite journal | vauthors = Vrba L, Futscher BW | title = Epigenetic Silencing of MORT Is an Early Event in Cancer and Is Associated with Luminal, Receptor Positive Breast Tumor Subtypes | journal = Journal of Breast Cancer | volume = 20 | issue = 2 | pages = 198–202 | date = June 2017 | pmid = 28690657 | doi = 10.4048/jbc.2017.20.2.198 }} </ref> Furthermore epigenetic silencing of ''MORT'' is associated with luminal, hormone receptor positive breast cancer, overexpression of the oncogene [[Cyclin D1|''CCND1'']], and ''[[GATA3]]'' mutations, but is negatively correlated with [[TP53|''p53'']] mutations<ref name="Vrba_2017" />. In summary, aberrant DNA hypermethylation-mediated epigenetic silencing of ''MORT'' occurs early during human [[carcinogenesis]] | Since cell immortality is an obligate feature of the cancer cell and ''MORT'' was discovered as a target of epigenetic silencing at the boundary where finite lifespan human cells transition from mortal to immortal, ''MORT’s'' epigenetic inactivation may create a cellular state permissive to cell immortalization and suggests a possible tumor suppressive mechanism of ''MORT''’s action. If this prediction is true, then epigenetic silencing of ''MORT'' should be an early identifiable lesion during human carcinogenesis and predicted to occur in premalignant lesions where cells have acquired pathologic immortality on their route to malignant transformation. Indeed, recent work has shown that ''MORT'' is epigenetically silenced in both [[Ductal carcinoma in situ|DCIS]], a premalignant lesion of invasive breast cancer, and colonic adenomas, a premalignant lesion of colon adenocarcinoma.<ref name="Vrba_2017">{{cite journal | vauthors = Vrba L, Futscher BW | title = Epigenetic Silencing of MORT Is an Early Event in Cancer and Is Associated with Luminal, Receptor Positive Breast Tumor Subtypes | journal = Journal of Breast Cancer | volume = 20 | issue = 2 | pages = 198–202 | date = June 2017 | pmid = 28690657 | doi = 10.4048/jbc.2017.20.2.198 | pmc=5500404}} </ref> Furthermore epigenetic silencing of ''MORT'' is associated with luminal, hormone receptor positive breast cancer, overexpression of the oncogene [[Cyclin D1|''CCND1'']], and ''[[GATA3]]'' mutations, but is negatively correlated with [[TP53|''p53'']] mutations<ref name="Vrba_2017" />. In summary, aberrant DNA hypermethylation-mediated epigenetic silencing of ''MORT'' occurs early during human [[carcinogenesis]] apparently coincident with when a mortal cell pathologically transitions to an immortal cell. | ||
== Cellular Function == | == Cellular Function == | ||
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 | 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 showing that ''MORT'' is enriched in the 100,000 g fraction, which contains polysomes, microsomes, endoplasmic reticulum, and the plasma membrane.<ref>{{cite book | vauthors = Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J | title = Molecular Cell Biology | edition = 4th | location = New York | publisher = W. H. Freeman | year = 2000 | url = https://www.ncbi.nlm.nih.gov/books/NBK21475/ | isbn = 978-0-7167-3136-8 }}</ref> Evidence is mounting that ''MORT'' acts as a regulator of protein translation through interactions with RNA binding proteins. | ||
== References == | == References == | ||
Latest revision as of 13:34, 9 March 2018
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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 to humans and great apes.[1] The MORT transcript is produced in all mortal cell types, but is lost in a large fraction of the most common human cancers 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) within a cluster of zinc finger genes (ZNF genes). The MORT gene consists of 2 exons, 260 and 1270 bp, respectively, that are separated by a 16 kbp intron. A large portion of the second MORT exon is formed by repetitive elements – two LINEs and an LTR element.[1] The MORT promoter is located in a CpG island that is shared with the ZNF667 gene; the two genes reside in a head to head orientation with one another. Despite the MORT gene's location inside a cluster of ZNF genes, the MORT gene is not homologous to any ZNF genes. While the MORT gene is in a head to head orientation with ZNF667, MORT does not overlap the ZNF667 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 expressed in these species.[1] Thus, from a 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 required evolution of additional genes with tumor suppressive activity, and that MORT is such an example.
Silencing in cancer
MORT is expressed in all 16 normal human tissues reported in the Illumina body map data,[2] as well as all in vitro cultured, finite lifespan, human cell strains that have been analyzed. 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[3] (totalling 17 different cancer types based on TCGA classification). Analysis shows that the MORT gene expression is silenced by DNA hypermethylation of its CpG island promoter in a majority of human tumor samples in 15 of these 17 human cancers.[1]
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.[1] MORT is silenced in cervical cancer and therefore may serve as an independent prognostic factor with low MORT expression be associated with a decreased overall survival.[4]
Since cell immortality is an obligate feature of the cancer cell and MORT was discovered as a target of epigenetic silencing at the boundary where finite lifespan human cells transition from mortal to immortal, MORT’s epigenetic inactivation may create a cellular state permissive to cell immortalization and suggests a possible tumor suppressive mechanism of MORT’s action. If this prediction is true, then epigenetic silencing of MORT should be an early identifiable lesion during human carcinogenesis and predicted to occur in premalignant lesions where cells have acquired pathologic immortality on their route to malignant transformation. Indeed, recent work has shown that MORT is epigenetically silenced in both DCIS, a premalignant lesion of invasive breast cancer, and colonic adenomas, a premalignant lesion of colon adenocarcinoma.[5] Furthermore epigenetic silencing of MORT is associated with luminal, hormone receptor positive breast cancer, overexpression of the oncogene CCND1, and GATA3 mutations, but is negatively correlated with p53 mutations[5]. In summary, aberrant DNA hypermethylation-mediated epigenetic silencing of MORT occurs early during human carcinogenesis apparently coincident with when a mortal cell pathologically transitions to an immortal cell.
Cellular Function
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 showing that MORT is enriched in the 100,000 g fraction, which contains polysomes, microsomes, endoplasmic reticulum, and the plasma membrane.[6] Evidence is mounting that MORT acts as a regulator of protein translation through interactions with RNA binding proteins.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 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. PMC 4844203. PMID 26646903.
- ↑ "MORT expression in Illumina Body Map Data".
- ↑ "Cancer Facts & Figures" (PDF). Atlanta: American Cancer Society. 2015.
- ↑ Zhao LP, Li RH, Han DM, Zhang XQ, Nian GX, Wu MX, Feng Y, Zhang L, Sun ZG (2017). "Independent prognostic Factor of low-expressed LncRNA ZNF667-AS1 for cervical cancer and inhibitory function on the proliferation of cervical cancer". European Review for Medical and Pharmacological Sciences. 21 (23): 5353–5360. doi:10.26355/eurrev_201712_13920. PMID 29243775.
- ↑ 5.0 5.1 Vrba L, Futscher BW (June 2017). "Epigenetic Silencing of MORT Is an Early Event in Cancer and Is Associated with Luminal, Receptor Positive Breast Tumor Subtypes". Journal of Breast Cancer. 20 (2): 198–202. doi:10.4048/jbc.2017.20.2.198. PMC 5500404. PMID 28690657.
- ↑ 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.