Rintasyöpä , C16- cer ja S1P keskiössä, mahdollisesti uusia terapiakohteita .

https://www.ncbi.nlm.nih.gov/pubmed/30226616

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Oncol Rep. 2018 Nov;40(5):2977-2987. doi: 10.3892/or.2018.6689. Epub 2018 Sep 7.

C16‑ceramide and sphingosine 1‑phosphate/S1PR2 have opposite effects on cell growth through mTOR signaling pathway regulation.

Kim MH¹, Park JW², Lee EJ³, Kim S⁴, Shin SH², Ahn JH², Jung Y⁵, Park I⁶, Park WJ³.

Author information

Abstract

Recently, sphingolipid derivatives, such as ceramide and sphingosine‑1‑phosphate (S1P), have emerged as key modulators in apoptotic cell death and cell proliferation. This study aimed to clarify the underlying signaling pathways of ceramide and S1P involved in breast cancer cell proliferation. Ceramide acyl chain length is determined by six mammalian ceramide synthases (CerS). We overexpressed CerS1 to 6 in MCF‑7 cells to examine whether ceramide signaling propagation varies as a function of acyl chain length. Among the six CerS, only CerS6 overexpression reduced phosphorylation of Akt, S6 kinase (S6K), and extracellular signal‑regulated kinases (ERK) as shown by western blotting. In addition, CerS6 overexpression reduced MCF‑7 cell proliferation. This effect was partially reversed by co‑treatment with MHY1485, an activator of mammalian target of rapamycin (mTOR), demonstrating an important role for the mTOR pathway in the CerS6‑mediated decrease in MCF‑7 cell proliferation. ERK inhibition, but not Akt inhibition, along with mTOR inhibition synergistically reduced MCF‑7 cell proliferation as measured by MTT assay. Notably, the expression of CerS6 and S1P receptor 2 (S1PR2), or CerS6 and sphingosine kinase 1 (SphK1), were negatively correlated according to the invasive breast carcinoma patient cohort in The Cancer Genome Atlas database. In addition, both SphK1 overexpression and S1P addition increased mTOR phosphorylation as shown by ELISA, while S1PR2 inhibition had the inverse effect. These data suggest that CerS6 and SphK1 regulate mTOR signaling in breast cancer cell proliferation. Moreover, mTOR activity can be regulated by the balance between S1P and C16‑ceramide, which is generated by CerS6

Keramidisyntaasit (CERS) ja sfingolipidien keramidien rasvahappopituuksien (N-acyl chain length) määrytyminen

https://www.ncbi.nlm.nih.gov/pubmed/29632068/
 J Biol Chem. 2018 Jun 22;293(25):9912-9921. doi: 10.1074/jbc.RA118.001936. Epub 2018 Apr 9.

Eleven residues determine the acyl chain specificity of ceramide synthases.

Tidhar R¹, Zelnik ID¹ et al. Abstract

Lipids display large structural complexity, with ∼40,000 different lipids identified to date, ∼4000 of which are sphingolipids. A critical factor determining the biological activities of the sphingolipid, ceramide, and of more complex sphingolipids is their N-acyl chain length, which in mammals is determined by a family of six ceramide synthases (CerS). Little information is available about the CerS regions that determine specificity toward different acyl-CoA substrates. We previously demonstrated that substrate specificity resides in a region of ∼150 residues in the Tram-Lag-CLN8 domain. Using site-directed mutagenesis and biochemical analyses, we now narrow specificity down to an 11-residue sequence in a loop located between the last two putative transmembrane domains (TMDs) of the CerS.
The specificity of a chimeric protein, CerS5^{(299-309→CerS2)}, based on the backbone of CerS5 (which generates C16-ceramide), but containing 11 residues from CerS2 (which generates C22-C24-ceramides), was altered such that it generated C22-C24 and other ceramides.
 Moreover, a chimeric protein, CerS4^{(291-301→CerS2)}, based on CerS4 (which normally generates C18-C22 ceramides) displayed significant activity toward C24:1-CoA.
Additional data supported the notion that substitutions of these 11 residues alter the specificities of the CerS toward their cognate acyl-CoAs.

Our findings may suggest that this short loop may restrict adjacent TMDs, leading to a more open conformation in the membrane, and that the CerS acting on shorter acyl-CoAs may have a longer, more flexible loop, permitting TMD flexibility. In summary, we have identified an 11-residue region that determines the acyl-CoA specificity of CerS. © 2018 Tidhar et al.

KEYWORDS: ceramide (Cer) ; ceramide synthase (CERS) ; lipid; membrane; sphingolipid

DOI:

10.1074/jbc.RA118.001936

Free PMC Article

http://www.jbc.org/content/293/25/9912

keramidien rasvahappopituuksien määräytyminen keramidisyntaasilla on kartoitettu 2018 aikoihin. On kuusi keramidisyntaasia. Israelissa ollaan tästä kiinnostuneita. 

Suomennosta artikkelista 3.1. 2019: 

LIPIDEILLA on laaja rakenteellinen kompleksisuutensa . Näihin mennessä on tunnistettu noin 40 000 erilaista lipidiä ja niistä kuuluu sfingolipidien luokkaan noin 4000 .
Kriittisenä tekijänä sfingolipidien, keramidien ja monimutkaisempien sfingolipidien biologisessa aktiivisuudessa on niiden aktivoituneiden  N-rasvahappojen (N-Acyl CoA) pituus;  imettäväisissä se määräytyy keramidisyntaasientsyymien avulla (CERS-perhe) Ihmisellä on kuusi CERS- entsyymiä CERS1- CERS6.
On olemassa vain vähän informaatiota siitä, mitkä CERS- entsyymin kohdat  määrittävät spesifisyyden eri rasvahappo-CoA- substraatteja kohtaan.
Aiemmin tämä tutkijaryhmä on osoittanut, että substraattispesifisyys on Tram- Lag-CLN8 domaanin 150:n aminohapon kohdalla.
 Käyttämällä kohdennettua mutageneesiä ja biokemiallisia analyysejä he nyt kaventavat spesifisyyden 11 aminohapon sekvenssiin eräässä silmukassa, joka sijaitsee kahden transmembraanisen domeenin (TMD) välissä keramidisyntaasissa (CERS) .

C16-keramidikokoa tuottavan CERS5 runkoon perustuva kimeerinen CerS5( 299-309 jakso-CerS2::sta). jossa on myös 11 aminohappoa CERS2 entsyymistä (joka taas tuottaa C22- C24 keramideja), aiheutti sellaisen muuntumisen CERS-spesifisyyteen, että tuottui C22- C24 - ja muita keramideja.

Lisäksi sellainen CERS4- perusteinen keramidisyntaasi ( jotka tuottaa normaalisti C18-C22 keramideja) muutettuna kimeeriseksi proteiiniksi CERS(291-301 jakso CERS2:sta) , osoittaa merkitsevää spesifisyyttä aktiivoitua C24:1- rasvahappoa (C24:1-CoA) kohtaan.

Lisätiedot tukevat havaintoa niden 11 aminohapon kyvystä muuntaa CERS entsyymien spesifisyyksiä niille tyypillisiä aktivoituja rasvahappoja kohtaan. Tutkijoiden havainnot viittanevat siihen, että tämä lyhyt silmukka rajoittanee toisiaan lähellä olevia transmembraanisia domaaneja (TMD) johtaen kalvon avoimempaan konfrontaatioon ja ne CERS entsyymit, jotka vaikuttavat lyhyehköihin aktivoituneisiin rasvahappoihin saattavat omata pidempiä, taipuvaisempia silmukoita sallien transmembraanidomaaneille joustoa. Yhteenvetona tutkijat ovat tunnistaneet 11 aminohapon alueen, joka määrittää CERS entsyymin spesifisyyden aktiivia rasvahappoa kohtaan.

Keramidisyntaasit 1-6 , CERS1- CERS6

CERS1(19p13.11) , EPM8, GDF1, LAG1, UOG1, GDF-1, LASS1.

Tämä  entsyymi tuottaa C18-keramideja  aivojen neuroneissa. Jos  geenin ilmentymä on koholla se merkitse  neuronin  pitkäikäisyyttä, kuntaas  alentunut ilmenemä assosioituu  myoklooniseen epilepsiaan.  ja dementiaan ihmisessä.

https://www.ncbi.nlm.nih.gov/gene/10715

Official Symbol

CERS1

Official Full Name

ceramide synthase 1

Also known as

EPM8; GDF1; LAG1; UOG1; GDF-1; LASS1

Summary

This gene encodes a ceramide synthase enzyme, which catalyzes the synthesis of ceramide, the hydrophobic moiety of sphingolipids. The encoded enzyme synthesizes 18-carbon (C18) ceramide in brain neurons. Elevated expression of this gene may be associated with increased longevity, while decreased expression of this gene may be associated with myoclonus epilepsy with dementia in human patients. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1. [provided by RefSeq, Jul 2016]

Expression

Biased expression in brain (RPKM 22.5) and testis (RPKM 5.1).

Preferred Names

ceramide synthase 1

Names

Embryonic growth/differentiation factor 1; (EPM8)

longevity assurance (LAG1, S. cerevisiae) homolog 1

longevity assurance gene 1 protein homolog 1 (LASS1)

protein UOG-1

upstream of GDF1; (UOG1)

CERS2  (1q21.3), TMSG1 (  Tuumormetastasis-suppressor gene 1 protein )

https://www.ncbi.nlm.nih.gov/gene/29956

Also known as

L3; LASS2; SP260; TMSG1

Summary

This gene encodes a protein that has sequence similarity to yeast longevity assurance gene 1. Mutation or overexpression of the related gene in yeast has been shown to alter yeast lifespan. The human protein may play a role in the regulation of cell growth. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

Expression

Ubiquitous expression in liver (RPKM 113.9), adrenal (RPKM 85.4) and 25 other tissues See more

Preferred Names

ceramide synthase 2

Names

LAG1 homolog, ceramide synthase 2

LAG1 longevity assurance 2

longevity assurance (LAG1, S. cerevisiae) homolog 2

sphingosine N-acyltransferase CERS2

tumor metastasis-suppressor gene 1 protein

( 299-309 aminohapot : FFGYYFFNSMM

ff
      301 gyyffnsmm) 

CERS3 (5q21.3), 

 https://www.ncbi.nlm.nih.gov/gene/204219

Also known as

ARCI9; LASS3

Summary

This gene is a member of the ceramide synthase family of genes. The ceramide synthase enzymes regulate sphingolipid synthesis by catalyzing the formation of ceramides from sphingoid base and acyl-coA substrates. This family member is involved in the synthesis of ceramides with ultra-long-chain acyl moieties (ULC-Cers), important to the epidermis in its role in creating a protective barrier from the environment. The protein encoded by this gene has also been implicated in modification of the lipid structures required for spermatogenesis. Mutations in this gene have been associated with male fertility defects, and epidermal defects, including ichthyosis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

Expression

Biased expression in skin (RPKM 15.5), esophagus (RPKM 13.5) and 1 other tissue See more

Preferred Names

ceramide synthase 3

Names

LAG1 homolog, ceramide synthase 3

LAG1 longevity assurance homolog 3

dihydroceramide synthase 3

sphingosine N-acyltransferase CERS3

NM_001290341.2 → NP_001277270.1  ceramide synthase 3 isoform 1

CERS4 (19p13.2),

 https://www.ncbi.nlm.nih.gov/gene/79603

Also known as

Trh1; LASS4

Expression

Ubiquitous expression in thyroid (RPKM 13.9), prostate (RPKM 10.3) and 24 other tissues See more

Orthologs

mouse all

CERS5 (12q13.12),

 https://www.ncbi.nlm.nih.gov/gene/91012

Also known as

Trh4; LASS5

Summary

This gene encodes a protein that belongs to the TLC (TRAM, LAG1 and CLN8 homology domains) family of proteins. The encoded protein functions in the synthesis of ceramide, a lipid molecule that is involved in a several cellular signaling pathways. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

Expression

Ubiquitous expression in endometrium (RPKM 6.0), placenta (RPKM 5.6) and 25 other tissues See more

Preferred Names

ceramide synthase 5

Names

LAG1 homolog, ceramide synthase 5

LAG1 longevity assurance homolog 5

TRAM homolog 4

sphingosine N-acyltransferase CERS5

 NM_001281731.1 → NP_001268660.1  ceramide synthase 5 isoform 2

J Biol Chem. 2008 Sep 26;283(39):26509-17. doi: 10.1074/jbc.M801597200. Epub 2008 Aug 1.

Ceramide generated by sphingomyelin hydrolysis and the salvage pathway is involved in hypoxia/reoxygenation-induced Bax redistribution to mitochondria in NT-2 cells.

Jin J¹, Hou Q, Mullen TD,et al.

CERS6 (2q24.3),

 https://www.ncbi.nlm.nih.gov/gene/253782

Also known as

CERS5; LASS6

Expression

Ubiquitous expression in colon (RPKM 18.1), thyroid (RPKM 16.4) and 25 other tissues See more

Preferred Names

ceramide synthase 6

Names

LAG1 homolog, ceramide synthase 6

longevity assurance homolog 6

NM_001256126.2 → NP_001243055.1  ceramide synthase 6 isoform 1.

TRAM, LAG1 and CLN8: members of a novel family of lipid-sensing domains?Trends Biochem. Sci. 2002 Aug ; 27(8):381-3

The human CERS6 gene promoter harbors a large CpG island (94 CpGs) and multiple transcription factor binding sites (TFBS), which support precise transcriptional regulation and signaling functions

Additional regulation is conferred by 15 microRNA
            (miRNA) target sites identified in the CERS6 3'-UTR region
            Publication Status: Online-Only

 JOURNAL   FASEB J. 24 (1), 296-308 (2010)
   PUBMED   19723703
  REMARK    GeneRIF: Mechanistically, regulation of ER-stress-induced apoptosis
            by CerS6/C(16)-ceramide was linked to the activation of a specific
            arm, ATF6/CHOP, of the unfolded protein response pathway.

 https://www.ncbi.nlm.nih.gov/pubmed/26887952