FATE1 explained

Fetal and Adult Testis-Expressed 1, encoded by the FATE1 gene in humans, is a protein identified as a cancer-testis antigen (CTA) in hepatocellular carcinomas and gastric and colon cancers.^{[1] [2] [3]} It is testis-specific in the fetus (aged 6 – 11 weeks). In adults, it is expressed predominantly in the testis and adrenal glands, with some expression in the lungs, heart, kidneys and throughout the brain.^{[4] [5]}

FATE1 is member of the Miff protein family, with its C-terminal domain, consisting of a transmembrane domain with a coiled-coil domain, showing high similarity to the mitochondrial fission factor (MFF) protein which is involved in mitochondrial and peroxisomal fission.

Gene location

FATE1 gene in humans is located on the long arm of the X chromosome at region 28, from base pair 150,884,502 to base pair 150,891,617.^[6]

Mechanism

It has been hypothesized that FATE1 uses its C-terminal transmembrane domain to attach to endoplasmic reticulum (ER) membrane and with its C-terminal coiled-coil domain it interacts with mitochondria.

FATE1 is localized in mitochondria-associated ER membranes (MAM) and modulates ER-mitochondria distance to regulate Ca²⁺- and drug dependent apoptosis in cancer cells.

FATE1 expression leads to reduction of Ca²⁺ uptake by mitochondria and therefore decrease in fragmentation of mitochondria, associated with mitochondrial Ca²⁺ uptake, consequently providing protection against cell death.^[7]

Relation to cancer

FATE1 is detectable in all cell lines derived from tumors, but is low or undetectable in telomere immortalized, non-tumorigenic fibroblasts and lung epithelial cells. FATE1 is suggested to be essential for survival of tumor cells as depletion of FATE1 results in viability reduction in melanoma, breast, prostate and sarcoma settings.^[8]

Upregulation of FATE1 by a transcription factor steroidogenic factor-1 (SF-1), involved in adrenal and gonadal development as well as in adrenocortical carcinoma, increases ER-mitochondria distance and is utilized by cancer cell to functionally uncouple ER and mitochondria.

Silencing FATE1 gene sensitizes non-small-cell lung cancer cell lines to paclitaxel, a chemotherapeutic drug against many different types of cancers.^[9]

Elevated level of FATE1 is found to be associated with higher mortality rate in colorectal cancers, but in non-small-cell lung cancers, elevation of FATE1 alone did not decrease chance of survival, but decreased if RNF183 expression is also increased.

Further reading

• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Olesen C, Hansen C, Bendsen E, Byskov AG, Schwinger E, Lopez-Pajares I, Jensen PK, Kristoffersson U, Schubert R, Van Assche E, Wahlstroem J, Lespinasse J, Tommerup N . Identification of human candidate genes for male infertility by digital differential display . Molecular Human Reproduction . 7 . 1 . 11–20 . January 2001 . 11134355 . 10.1093/molehr/7.1.11 . free .
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Reports . 1 . 3 . 287–92 . September 2000 . 11256614 . 1083732 . 10.1093/embo-reports/kvd058 .
• Olesen C, Silber J, Eiberg H, Ernst E, Petersen K, Lindenberg S, Tommerup N . Mutational analysis of the human FATE gene in 144 infertile men . Human Genetics . 113 . 3 . 195–201 . August 2003 . 12811541 . 10.1007/s00439-003-0974-9 . 10268 .
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415-8 . January 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–14 . May 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . free .

Notes and References

1. Olesen C, Larsen NJ, Byskov AG, Harboe TL, Tommerup N . Human FATE is a novel X-linked gene expressed in fetal and adult testis . Molecular and Cellular Endocrinology . 184 . 1–2 . 25–32 . November 2001 . 11694338 . 10.1016/S0303-7207(01)00666-9 . 26552615 .
2. Web site: Entrez Gene: FATE1 fetal and adult testis expressed 1.
3. Doghman-Bouguerra M, Granatiero V, Sbiera S, Sbiera I, Lacas-Gervais S, Brau F, Fassnacht M, Rizzuto R, Lalli E . FATE1 antagonizes calcium- and drug-induced apoptosis by uncoupling ER and mitochondria . EMBO Reports . 17 . 9 . 1264–80 . September 2016 . 27402544 . 5007562 . 10.15252/embr.201541504 .
4. Dong XY, Su YR, Qian XP, Yang XA, Pang XW, Wu HY, Chen WF . Identification of two novel CT antigens and their capacity to elicit antibody response in hepatocellular carcinoma patients . British Journal of Cancer . 89 . 2 . 291–7 . July 2003 . 12865919 . 2394243 . 10.1038/sj.bjc.6601062 .
5. Yang XA, Dong XY, Qiao H, Wang YD, Peng JR, Li Y, Pang XW, Tian C, Chen WF . Immunohistochemical analysis of the expression of FATE/BJ-HCC-2 antigen in normal and malignant tissues . Laboratory Investigation; A Journal of Technical Methods and Pathology . 85 . 2 . 205–13 . February 2005 . 15580283 . 10.1038/labinvest.3700220 . free .
6. Web site: AceView: Gene:FATE1, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView.. Danielle Thierry-Mieg and Jean Thierry-Mieg, NCBI/NLM/NIH. www.ncbi.nlm.nih.gov. 2018-11-09.
7. Szabadkai G, Simoni AM, Bianchi K, De Stefani D, Leo S, Wieckowski MR, Rizzuto R . Mitochondrial dynamics and Ca2+ signaling . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1763 . 5–6 . 442–9 . 2006-05-01 . 16750865 . 10.1016/j.bbamcr.2006.04.002 . free .
8. Maxfield KE, Taus PJ, Corcoran K, Wooten J, Macion J, Zhou Y, Borromeo M, Kollipara RK, Yan J, Xie Y, Xie XJ, Whitehurst AW . Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer . En . Nature Communications . 6 . 1 . 8840 . November 2015 . 26567849 . 10.1038/ncomms9840 . 4660212 . 2015NatCo...6.8840M .
9. Whitehurst AW, Bodemann BO, Cardenas J, Ferguson D, Girard L, Peyton M, Minna JD, Michnoff C, Hao W, Roth MG, Xie XJ, White MA . Synthetic lethal screen identification of chemosensitizer loci in cancer cells . Nature . 446 . 7137 . 815–9 . April 2007 . 17429401 . 10.1038/nature05697 . 2007Natur.446..815W . 4366273 .