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MTDH

From Wikipedia, the free encyclopedia

MTDH
Identifiers
AliasesMTDH, 3D3, AEG-1, AEG1, LYRIC, LYRIC/3D3, metadherin
External IDsOMIM: 610323; MGI: 1914404; GeneCards: MTDH
Available structures
PDBOrtholog search: PDBe RCSB
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

92140

67154

Ensembl

ENSG00000147649

ENSMUSG00000022255

UniProt

Q86UE4

Q80WJ7

RefSeq (mRNA)

NM_178812
NM_001363136
NM_001363137
NM_001363138
NM_001363139

NM_026002
NM_001357925
NM_001357926

RefSeq (protein)

NP_848927
NP_001350065
NP_001350066
NP_001350067
NP_001350068

NP_080278
NP_001344854
NP_001344855

Location (UCSC)Chr 8: 97.64 – 97.73 MbChr 15: 34.08 – 34.15 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Metadherin, also known as protein LYRIC or astrocyte elevated gene-1 protein (AEG-1) is a protein that in humans is encoded by the MTDH gene.[5][6][7]

Function

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MTDH (AEG-1) is involved in HIF-1alpha mediated angiogenesis. MTDH also interacts with SND1 and involved in RNA-induced silencing complex (RISC) and plays very important role in RISC and miRNA functions.[8][9] MTDH has been shown to interact with spliceosome proteins in the cell nucleus and regulate the process of alternative splicing.[10]

MTDH induces an oncogene called Late SV40 factor (LSF/TFCP2) which is involved in thymidylate synthase (TS) induction and DNA biosynthesis synthesis.[11] Late SV40 factor (LSF/TFCP2) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP9).[12]

Clinical significance

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MTDH acts as an oncogene in melanoma, malignant glioma, breast cancer and hepatocellular carcinoma.[13] It is highly expressed in these cancers and helps in their progression and development. It is induced by c-Myc oncogene and plays an important role in anchorage independent growth of cancer cells (metastasis).

Elevated expression of MTDH, which is overexpressed in more than 40% of breast cancers, is associated with poor clinical outcomes. MTDH has a dual role in promoting metastatic seeding and enhancing chemoresistance. MTDH is therefore a potential therapeutic target for enhancing chemotherapy and reducing metastasis.[14][15][16][17]

MTDH has been shown to be overexpressed in prostate cancer, where there is a shift towards a more cytoplasmic localisation, signalling a poor prognosis.[18][19] In the nucleus of prostate cancer cells, MTDH has been shown to affect alternative splicing of genes such as CD44, which may also be associated with prostate cancer progression.[10]

LSF/TFCP2 plays a multifaceted role in chemo resistance, EMT, allergic response, inflammation and Alzheimer's disease.[20]

MTDH controls many hallmarks of oncogenes and cancer. MTDH/AEG-1 induces hepato steatosis in mouse liver.[21] MTDH knockdown by artificial microRNA interference functions as a potential tumor suppressor in breast cancer.[22] Astrocyte elevated gene-1/MTDH undergoes palmitoylation in normal and abnormal cell physiology.[23] Biomaterial titanium substrata with microgrooves can alter MTDH expression in human primary cells.[24]

Interactions

[edit]

MTDH has been shown to interact with:

References

[edit]
  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000147649 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022255 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: MTDH metadherin".
  6. ↑ Brown DM, Ruoslahti E (April 2004). "Metadherin, a cell surface protein in breast tumors that mediates lung metastasis". Cancer Cell. 5 (4): 365–374. doi:10.1016/S1535-6108(04)00079-0. PMID 15093543.
  7. ↑ Sutherland HG, Lam YW, Briers S, Lamond AI, Bickmore WA (March 2004). "3D3/lyric: a novel transmembrane protein of the endoplasmic reticulum and nuclear envelope, which is also present in the nucleolus". Experimental Cell Research. 294 (1): 94–105. doi:10.1016/j.yexcr.2003.11.020. PMID 14980505.
  8. ↑ Yoo BK, Santhekadur PK, Gredler R, Chen D, Emdad L, Bhutia S, et al. (May 2011). "Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma". Hepatology. 53 (5). Baltimore, Md.: 1538–1548. doi:10.1002/hep.24216. PMC 3081619. PMID 21520169.
  9. ↑ Yoo BK, Emdad L, Lee SG, Su ZZ, Santhekadur P, Chen D, et al. (April 2011). "Astrocyte elevated gene-1 (AEG-1): A multifunctional regulator of normal and abnormal physiology". Pharmacology & Therapeutics. 130 (1): 1–8. doi:10.1016/j.pharmthera.2011.01.008. PMC 3043119. PMID 21256156.
  10. 1 2 Luxton HJ, Simpson BS, Mills IG, Brindle NR, Ahmed Z, Stavrinides V, et al. (September 2019). "The Oncogene Metadherin Interacts with the Known Splicing Proteins YTHDC1, Sam68 and T-STAR and Plays a Novel Role in Alternative mRNA Splicing". Cancers. 11 (9). Basel: 1233. doi:10.3390/cancers11091233. PMC 6770463. PMID 31450747.
  11. ↑ Yoo BK, Gredler R, Vozhilla N, Su ZZ, Chen D, Forcier T, et al. (August 2009). "Identification of genes conferring resistance to 5-fluorouracil". Proceedings of the National Academy of Sciences of the United States of America. 106 (31): 12938–12943. Bibcode:2009PNAS..10612938Y. doi:10.1073/pnas.0901451106. PMC 2722317. PMID 19622726.
  12. ↑ Santhekadur PK, Gredler R, Chen D, Siddiq A, Shen XN, Das SK, et al. (January 2012). "Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP-9)". The Journal of Biological Chemistry. 287 (5): 3425–3432. doi:10.1074/jbc.M111.298976. PMC 3270996. PMID 22167195.
  13. ↑ Yoo BK, Emdad L, Su ZZ, Villanueva A, Chiang DY, Mukhopadhyay ND, et al. (March 2009). "Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression". The Journal of Clinical Investigation. 119 (3): 465–477. doi:10.1172/JCI36460. PMC 2648696. PMID 19221438.
  14. ↑ Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, et al. (January 2009). "MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer". Cancer Cell. 15 (1): 9–20. doi:10.1016/j.ccr.2008.11.013. PMC 2676231. PMID 19111877.
  15. ↑ Shen M, Wei Y, Kim H, Wan L, Jiang YZ, Hang X, et al. (2021-11-29). "Small-molecule inhibitors that disrupt the MTDH–SND1 complex suppress breast cancer progression and metastasis". Nature Cancer. 3 (1): 43–59. doi:10.1038/s43018-021-00279-5. ISSN 2662-1347. PMC 8818087. PMID 35121987.
  16. ↑ Shen M, Smith HA, Wei Y, Jiang YZ, Zhao S, Wang N, et al. (2021-11-29). "Pharmacological disruption of the MTDH–SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer". Nature Cancer. 3 (1): 60–74. doi:10.1038/s43018-021-00280-y. ISSN 2662-1347. PMC 8818088. PMID 35121988.
  17. ↑ "New cancer therapy from Yibin Kang's lab holds potential to switch off major cancer types without side effects". Princeton University. Retrieved 2021-12-10.
  18. ↑ Dhiman G, Srivastava N, Goyal M, Rakha E, Lothion-Roy J, Mongan NP, et al. (2019). "Metadherin: A Therapeutic Target in Multiple Cancers". Frontiers in Oncology. 9 349. doi:10.3389/fonc.2019.00349. PMC 6509227. PMID 31131259.
  19. ↑ Thirkettle HJ, Girling J, Warren AY, Mills IG, Sahadevan K, Leung H, et al. (May 2009). "LYRIC/AEG-1 is targeted to different subcellular compartments by ubiquitinylation and intrinsic nuclear localization signals". Clinical Cancer Research. 15 (9): 3003–3013. doi:10.1158/1078-0432.CCR-08-2046. PMID 19383828.
  20. ↑ Santhekadur PK, Rajasekaran D, Siddiq A, Gredler R, Chen D, Schaus SC, et al. (2012). "The transcription factor LSF: a novel oncogene for hepatocellular carcinoma" (PDF). American Journal of Cancer Research. 2 (3): 269–285. PMC 3365805. PMID 22679558.
  21. ↑ Srivastava J, Siddiq A, Emdad L, Santhekadur PK, Chen D, Gredler R, et al. (November 2012). "Astrocyte elevated gene-1 promotes hepatocarcinogenesis: novel insights from a mouse model". Hepatology. 56 (5). Baltimore, Md.: 1782–1791. doi:10.1002/hep.25868. PMC 3449036. PMID 22689379.
  22. ↑ Wang S, Shu JZ, Cai Y, Bao Z, Liang QM (2012). "Establishment and characterization of MTDH knockdown by artificial MicroRNA interference - functions as a potential tumor suppressor in breast cancer". Asian Pacific Journal of Cancer Prevention. 13 (6): 2813–2818. doi:10.7314/apjcp.2012.13.6.2813. PMID 22938464.
  23. ↑ Martin BR, Wang C, Adibekian A, Tully SE, Cravatt BF (November 2011). "Global profiling of dynamic protein palmitoylation". Nature Methods. 9 (1): 84–89. doi:10.1038/nmeth.1769. PMC 3248616. PMID 22056678.
  24. ↑ Lee MH, Kang JH, Lee SW (April 2012). "The significance of differential expression of genes and proteins in human primary cells caused by microgrooved biomaterial substrata". Biomaterials. 33 (11): 3216–3234. doi:10.1016/j.biomaterials.2012.01.034. PMID 22285466.
  25. ↑ Lee SJ, Choi KM, Bang G, Park SG, Kim EB, Choi JW, et al. (June 2021). "Identification of Nucleolin as a Novel AEG-1-Interacting Protein in Breast Cancer via Interactome Profiling". Cancers. 13 (11). Basel: 2842. doi:10.3390/cancers13112842. PMC 8201222. PMID 34200450. S2CID 235436955.
  26. ↑ Neeli PK, Gollavilli PN, Mallappa S, Hari SG, Kotamraju S (March 2020). "A novel metadherinΔ7 splice variant enhances triple negative breast cancer aggressiveness by modulating mitochondrial function via NFĸB-SIRT3 axis". Oncogene. 39 (10): 2088–2102. doi:10.1038/s41388-019-1126-6. PMID 31806873. S2CID 208648747.

Further reading

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