MTDH
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.[1][2][3]
Function
AEG-1 is involved in HIF-1alpha mediated angiogenesis. AEG-1 also interacts with SND1 and involved in RNA-induced silencing complex (RISC) and plays very important role in RISC and miRNA functions.[4][5]
AEG-1 induces an oncogene called Late SV40 factor (LSF/TFCP2) which is involved in thymidylate synthase (TS) induction and DNA biosynthesis synthesis.[6] Late SV40 factor (LSF/TFCP2) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP9).[7]
Clinical significance
AEG-1 acts as an oncogene in melanoma, malignant glioma, breast cancer and hepatocellular carcinoma.[8] It is highly expressed in these cancers and helps in progression and development of these cancers. It is induced by c-Myc oncogene and plays very important role in anchorage independent growth of cancer cells.
Elevated expression of the metastasis gene metadherin (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.[9]
LSF/TFCP2 plays multifaceted role in chemo resistance, EMT, allergic response, inflammation and Alzheimer’s disease.[10]
AEG-1 controls many hallmarks of oncogenes and cancer. AEG-1/MTDH induces hepato steatosis in mouse liver.[11] The MTDH knockdown by artificial microRNA interference functions as a potential tumor suppressor in breast cancer.[12] Astrocyte elevated gene-1/MTDH undergoes palmitoylation in normal and abnormal physiology of the cell [13].The microgrooved biomaterial titanium substrata can alter the expression of AEG-1 in human primary cells [14].
References
- ↑ "Entrez Gene: MTDH metadherin".
- ↑ Brown DM, Ruoslahti E (April 2004). "Metadherin, a cell surface protein in breast tumors that mediates lung metastasis". Cancer Cell 5 (4): 365–74. doi:10.1016/S1535-6108(04)00079-0. PMID 15093543.
- ↑ 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". Exp. Cell Res. 294 (1): 94–105. doi:10.1016/j.yexcr.2003.11.020. PMID 14980505.
- ↑ Yoo BK, Santhekadur PK, Gredler R, Chen D, Emdad L, Bhutia SK, Pannell L, Fisher PB, Sarkar D (2011). "Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma". Hepatology 53 (5): 1538–1548. doi:10.1002/hep.24216. PMC 3081619. PMID 21520169.
- ↑ Yoo BK, Emdad L, Lee SG, Su ZZ, Santhekadur P, Chen D, Gredler R, Fisher PB, Sarkar D (January 2011). "Astrocyte elevated gene-1 (AEG-1): A multifunctional regulator of normal and abnormal physiology". Pharmacol Ther 130 (1): 1–8. doi:10.1016/j.pharmthera.2011.01.008. PMC 3043119. PMID 21256156.
- ↑ Yoo BK, Gredler R, Vozhilla N, Su ZZ, Chen D, Forcier T, Shah K, Saxena U, Hansen U, Fisher PB, Sarkar D (August 2009). "Identification of genes conferring resistance to 5-fluorouracil". Proc. Natl. Acad. Sci. U.S.A. 106 (31): 12938–43. doi:10.1073/pnas.0901451106. PMC 2722317. PMID 19622726.
- ↑ Santhekadur PK, Gredler R, Chen D, Siddiq A, Shen XN, Das SK, Emdad L, Fisher PB, Sarkar D (January 2012). "Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP-9)". J. Biol. Chem. 287 (5): 3425–32. doi:10.1074/jbc.M111.298976. PMC 3270996. PMID 22167195.
- ↑ Yoo BK, Emdad L, Su ZZ, Villanueva A, Chiang DY, Mukhopadhyay ND, Mills AS, Waxman S, Fisher RA, Llovet JM, Fisher PB, Sarkar D (March 2009). "Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression". J. Clin. Invest. 119 (3): 465–77. doi:10.1172/JCI36460. PMC 2648696. PMID 19221438.
- ↑ Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, Reiss M, Au JL, Haffty BG, Kang Y (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.
- ↑ Santhekadur PK, Rajasekaran D, Siddiq A, Gredler R, Chen D, Schaus SC, Hansen U, Fisher PB, Sarkar D (2012). "The transcription factor LSF: a novel oncogene for hepatocellular carcinoma". Am J Cancer Res 2 (3): 269–285.
- ↑ Srivastava J, Siddiq A, Emdad L, Santhekadur PK, Chen D, Gredler R, Shen XN, Dumur CL, Hylemon PB, Mukhopadhyay ND, Bhere D, Shah K, Ahmad R, Giashuddin S, Stafflinger J, Subler MA, Windle JJ, Fisher PB, Sarkar D (June 2012). "Astrocyte elevated gene-1 (AEG-1) promotes hepatocarcinogenesis: Novel insights from a mouse model". Hepatology. doi:10.1002/hep.25868. PMID 22689379.
- ↑ 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 Pac. J. Cancer Prev. 13 (6): 2813–8. PMID 22938464.
13. Martin BR, Wang C, Adibekian A, Tully SE, Cravatt BF.Global profiling of dynamic protein palmitoylation. Nat Methods. 2011 Nov 6;9(1):84-9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248616/pdf/nihms331894.pdf.
14. Lee MH, Kang JH, Lee SW. The significance of differential expression of genes and proteins in human primary cells caused by microgrooved biomaterial substrata.Biomaterials. 2012 Apr;33(11):3216-34.
Further reading
- Emdad L, Sarkar D, Su ZZ, et al. (2007). "Astrocyte elevated gene-1: recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration". Pharmacol. Ther. 114 (2): 155–70. doi:10.1016/j.pharmthera.2007.01.010. PMC 2039930. PMID 17397930.
- van 't Veer LJ, Dai H, van de Vijver MJ, et al. (2002). "Gene expression profiling predicts clinical outcome of breast cancer". Nature 415 (6871): 530–6. doi:10.1038/415530a. PMID 11823860.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- Sutherland HG, Lam YW, Briers S, et al. (2004). "3D3/lyric: a novel transmembrane protein of the endoplasmic reticulum and nuclear envelope, which is also present in the nucleolus". Exp. Cell Res. 294 (1): 94–105. doi:10.1016/j.yexcr.2003.11.020. PMID 14980505.
- Brown DM, Ruoslahti E (2004). "Metadherin, a cell surface protein in breast tumors that mediates lung metastasis". Cancer Cell 5 (4): 365–74. doi:10.1016/S1535-6108(04)00079-0. PMID 15093543.
- Britt DE, Yang DF, Yang DQ, et al. (2004). "Identification of a novel protein, LYRIC, localized to tight junctions of polarized epithelial cells". Exp. Cell Res. 300 (1): 134–48. doi:10.1016/j.yexcr.2004.06.026. PMID 15383321.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Kang DC, Su ZZ, Sarkar D, et al. (2005). "Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1". Gene 353 (1): 8–15. doi:10.1016/j.gene.2005.04.006. PMID 15927426.
- Olsen JV, Blagoev B, Gnad F, et al. (2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
- Lee SG, Su ZZ, Emdad L, et al. (2007). "Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc". Proc. Natl. Acad. Sci. U.S.A. 103 (46): 17390–5. doi:10.1073/pnas.0608386103. PMC 1859939. PMID 17088530.