Ceramide synthase 1
Ceramide synthase 1 also known as LAG1 longevity assurance homolog 1 is an enzyme that in humans is encoded by the CERS1 gene.[1][2][3]
Function
This gene encodes a member of the bone morphogenetic protein (BMP) family and the TGF-beta superfamily. This group of proteins is characterized by a polybasic proteolytic processing site that is cleaved to produce a mature protein containing seven conserved cysteine residues. Members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Studies in yeast suggest that the encoded protein is involved in aging. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1.[3]
Ceramide synthase 1 (CerS1) is a ceramide synthase that catalyzes the synthesis of C18 ceramide in a fumonisin B1-independent manner, and it primarily expressed in the brain.[4] It can also be found in low levels in skeletal muscle and the testis.[5] Within the cell, CerS1 is located in the endoplasmic reticulum (ER) and golgi apparatus membrane. CerS1 has two isoforms and isoform 1 may recycle from the golgi to the ER.[6]
CerS1/GDF1 mRNA is strongly expressed in muscle and brain, and was also found in heart and lung.[7] Within the brain, CerS1 is the primary CerS expressed in most neurons. In white matter, it can only be found in low levels.[5][8]
In a recent experiment performed in mice in 2012, ablation of neuronal CerS1 decreased levels of sphingolipids, hexosylceramides, and sphingomyelin. Although the brains in these mice appeared to develop normally, researchers observed atrophy of the cerebellum, and Purkinje neurons appeared to degenerate. Granule cells also showed a 6 times increased rate of apoptosis. Behaviorally, the mice expressed motor and neurophysiological impairment. [4]
Structure
Unlike other mammalian ceramides, CerS1 does not appear to have a Hox-like domain. It is functionally and structurally distinct from other CerS and is found in an entirely different branch of the phylogenetic tree.[5]
Clinical significance
On application of various stresses, CerS1 turns over rapidly by ubiquitination and proteasomal degradation, suggesting that is has a short half life.[5]
It has been suggested that CerS1 is involved with the regulation of the growth of head and neck squamous cell carcinoma (HNSCC), based on the information that C18 ceramide levels are lower in HNSCC tissues than in normal tissue. CerS1, in particular amongst other CerS, has also been shown to sensitize cells to chemotherapeutic drugs, such as cisplatin, carboplatin, doxorubicin, and vincristine.[5]
References
- ↑ Jiang JC, Kirchman PA, Zagulski M, Hunt J, Jazwinski SM (Jun 1999). "Homologs of the yeast longevity gene LAG1 in Caenorhabditis elegans and human". Genome Res 8 (12): 1259–72. doi:10.1101/gr.8.12.1259. PMID 9872981.
- ↑ Lee SJ (Jun 1991). "Expression of growth/differentiation factor 1 in the nervous system: conservation of a bicistronic structure". Proc Natl Acad Sci U S A 88 (10): 4250–4. doi:10.1073/pnas.88.10.4250. PMC 51636. PMID 2034669.
- 1 2 "Entrez Gene: LASS1 LAG1 homolog, ceramide synthase 1 (S. cerevisiae)".
- 1 2 Ginkel C, Hartmann D, vom Dorp K, Zlomuzica A, Farwanah H, Eckhardt M, Sandhoff R, Degen J, Rabionet M, Dere E, Dörmann P, Sandhoff K, Willecke K (December 2012). "Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes". J. Biol. Chem. 287 (50): 41888–902. doi:10.1074/jbc.M112.413500. PMC 3516736. PMID 23074226.
- 1 2 3 4 5 Levy M, Futerman AH (May 2010). "Mammalian ceramide synthases". IUBMB Life 62 (5): 347–56. doi:10.1002/iub.319. PMC 2858252. PMID 20222015.
- ↑ "Ceramide synthase 1". EBI.ac.uk. EMBL-EBI. 2014. Retrieved 16 February 2014.
- ↑ Riebeling C, Allegood JC, Wang E, Merrill AH Jr, Futerman AH (Oct 2003). "Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors". J Biol Chem 278 (44): 43452–9. doi:10.1074/jbc.M307104200. PMID 12912983.
- ↑ Becker I, Wang-Eckhardt L, Yaghootfam A, Gieselmann V, Eckhardt M (February 2008). "Differential expression of (dihydro)ceramide synthases in mouse brain: oligodendrocyte-specific expression of CerS2/Lass2". Histochemistry and Cell Biology 129 (2): 233–41. doi:10.1007/s00418-007-0344-0. PMID 17901973.
Further reading
- 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.
- Koybasi S, Senkal CE, Sundararaj K; et al. (2004). "Defects in cell growth regulation by C18:0-ceramide and longevity assurance gene 1 in human head and neck squamous cell carcinomas". J. Biol. Chem. 279 (43): 44311–9. doi:10.1074/jbc.M406920200. PMID 15317812.
- Grimwood J, Gordon LA, Olsen A; et al. (2004). "The DNA sequence and biology of human chromosome 19". Nature 428 (6982): 529–35. doi:10.1038/nature02399. PMID 15057824.
- 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.
- Venkataraman K, Riebeling C, Bodennec J; et al. (2002). "Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells". J. Biol. Chem. 277 (38): 35642–9. doi:10.1074/jbc.M205211200. PMID 12105227.
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