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Gene Review

GREM1  -  gremlin 1, DAN family BMP antagonist

Homo sapiens

Synonyms: C15DUPq, CKTSF1B1, CRAC1, CRCS4, Cell proliferation-inducing gene 2 protein, ...
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Disease relevance of GREM1


Psychiatry related information on GREM1

  • Two experiments using the DRM paradigm (Deese, 1959; Roediger & McDermott, 1995) explored the influence of manipulating the number of associates studied, study item presentation frequency, backward associative strength, and study time on error-inflating and error-editing processes separately by examining speeded and unspeeded recognition decisions [5].

High impact information on GREM1


Chemical compound and disease context of GREM1

  • Gremlin messenger RNA levels correlated directly with renal dysfunction, determined by means of serum creatinine level, but not with proteinuria level [9].
  • The nucleoside transport inhibitor dipyridamole can increase the cytotoxicity of 5-fluorouracil in a human colon cancer cell line (HCT 116) without affecting the total amount of fluorouracil incorporated into the acid soluble and insoluble fractions (J. L. Grem and P. H. Fischer, Cancer Res., 45: 2967-2972, 1985) [10].
  • Gremlin mRNA levels were correlated, by RT-PCR, with other genes implicated in the pathogenesis of diabetic retinopathy and the signalling pathways in high glucose induced gremlin expression were probed using physiological inhibitors [11].
  • The purpose of this study was to determine the potential toxicity of docosahexaenoic acid-rich microalgae from Schizochytrium sp. (DRM), administered in the diet to rats for at least 13 weeks [12].
  • DRM was not mutagenic in the Ames reverse mutation assay using five different Salmonella histidine auxotroph tester strains [13].

Biological context of GREM1

  • CONCLUSION: PTGS2, HAS2 and GREM1 gene expression correlates to morphological and physiological characteristics and provides a novel approach to predict human embryo development [14].
  • Analysis of Gremlin-/- and Dkk-/- mouse mutants and local treatments with BMP proteins reveal that the expression of cathepsin B and D genes is regulated by BMP signaling, a pathway responsible for triggering cell death [15].
  • In vivo bromodeoxyuridine labeling and marrow stromal cell cultures demonstrated an inhibitory effect of gremlin on osteoblastic cell replication, but no change on apoptosis was detected [4].
  • Marrow stromal cells from gremlin transgenics displayed a reduced response to BMP on phosphorylated mothers against decapentaplegic 1/5/8 phosphorylation and reduced free cytosolic beta-catenin levels [4].
  • To investigate the actions of gremlin on bone remodeling in vivo, we generated transgenic mice overexpressing gremlin under the control of the osteocalcin promoter [4].

Anatomical context of GREM1

  • IHG-2, a mesangial cell gene induced by high glucose, is human gremlin. Regulation by extracellular glucose concentration, cyclic mechanical strain, and transforming growth factor-beta1 [16].
  • The loss of DRM/Gremlin mRNA expression in human cancer cell lines is associated with DNA methylation, and treatment with the methylation inhibitor-reactivated mRNA expression (n=13) [1].
  • HAS2 and GREM1 expression was also higher from the cumulus surrounding oocytes that gave rise to higher grade embryos (P<0.001) [14].
  • Lung fibroblasts isolated from IPF patients also expressed elevated levels of gremlin, which was associated with impaired responsiveness to endogenous and exogenous BMP-4 [3].
  • Transforming growth factor-beta-induced epithelial-to-mesenchymal transition of A549 lung epithelial cells in culture was also associated with induction of gremlin mRNA expression [3].

Associations of GREM1 with chemical compounds

  • In contrast, dexamethasone (DEX) blocked the effects of the BMPs on SOST and gremlin, but not on noggin [17].
  • Gremlin is a 184 amino acid protein and a member of the cysteine knot superfamily [18].
  • The SOST gene encodes a protein that shares similarity with a class of cystine knot-containing factors including dan, cerberus, gremlin, prdc, and caronte [19].
  • We report here that a low-density Triton X-100-insoluble membrane (detergent-resistant membrane; DRM) fraction is present in bovine rod photoreceptor outer segments (ROS) [20].
  • A cholesterol-removing reagent, methyl-beta-cyclodextrin, selectively but partially solubilized PDE from the DRM, suggesting that cholesterol contributes, at least in part, to the association of PDE with the DRM [20].

Physical interactions of GREM1


Regulatory relationships of GREM1


Other interactions of GREM1

  • We used cloning in silico coupled with polymerase chain reaction to demonstrate that IHG-2 is part of the 3'-untranslated region of gremlin, a member of the DAN family of secreted proteins that antagonize the bioactivities of members of the transforming growth factor (TGF)-beta superfamily [16].
  • The expression of PTGS2 and HAS2 was 6-fold higher, and that of GREM1 was 15-fold higher in cumulus yielding higher grade embryos versus lower grade embryos [14].
  • Evidence will be presented that mesangial cell gremlin expression is up-regulated by high ambient glucose, cyclic mechanical strain and transforming growth factor-beta (TGF-beta) and that gremlin may be an important modulator of mesangial cell proliferation and epithelial-mesenchymal transdifferentiation in a diabetic milieu [18].
  • The levels of noggin and, to a lesser extent, gremlin were also increased by BMPs [17].
  • In this review, we will focus on the potential role of one such differentially expressed gene, namely gremlin, in the pathogenesis of diabetic nephropathy [18].

Analytical, diagnostic and therapeutic context of GREM1


  1. DNA methylation-associated inactivation of TGFbeta-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers. Suzuki, M., Shigematsu, H., Shames, D.S., Sunaga, N., Takahashi, T., Shivapurkar, N., Iizasa, T., Frenkel, E.P., Minna, J.D., Fujisawa, T., Gazdar, A.F. Br. J. Cancer (2005) [Pubmed]
  2. Transcriptional profiling reveals novel markers of liver fibrogenesis: gremlin and insulin-like growth factor-binding proteins. Boers, W., Aarrass, S., Linthorst, C., Pinzani, M., Elferink, R.O., Bosma, P. J. Biol. Chem. (2006) [Pubmed]
  3. Bone morphogenetic protein-4 inhibitor gremlin is overexpressed in idiopathic pulmonary fibrosis. Koli, K., Myllärniemi, M., Vuorinen, K., Salmenkivi, K., Ryynänen, M.J., Kinnula, V.L., Keski-Oja, J. Am. J. Pathol. (2006) [Pubmed]
  4. Skeletal overexpression of gremlin impairs bone formation and causes osteopenia. Gazzerro, E., Pereira, R.C., Jorgetti, V., Olson, S., Economides, A.N., Canalis, E. Endocrinology (2005) [Pubmed]
  5. An examination of two-process theories of false recognition. Arndt, J., Gould, C. Memory (Hove, England) (2006) [Pubmed]
  6. Antagonists of Wnt and BMP signaling promote the formation of vertebrate head muscle. Tzahor, E., Kempf, H., Mootoosamy, R.C., Poon, A.C., Abzhanov, A., Tabin, C.J., Dietrich, S., Lassar, A.B. Genes Dev. (2003) [Pubmed]
  7. Regulation of myogenic progenitor proliferation in human fetal skeletal muscle by BMP4 and its antagonist Gremlin. Frank, N.Y., Kho, A.T., Schatton, T., Murphy, G.F., Molloy, M.J., Zhan, Q., Ramoni, M.F., Frank, M.H., Kohane, I.S., Gussoni, E. J. Cell Biol. (2006) [Pubmed]
  8. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Sneddon, J.B., Zhen, H.H., Montgomery, K., van de Rijn, M., Tward, A.D., West, R., Gladstone, H., Chang, H.Y., Morganroth, G.S., Oro, A.E., Brown, P.O. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  9. Expression of gremlin, a bone morphogenetic protein antagonist, in human diabetic nephropathy. Dolan, V., Murphy, M., Sadlier, D., Lappin, D., Doran, P., Godson, C., Martin, F., O'Meara, Y., Schmid, H., Henger, A., Kretzler, M., Droguett, A., Mezzano, S., Brady, H.R. Am. J. Kidney Dis. (2005) [Pubmed]
  10. Alteration of fluorouracil metabolism in human colon cancer cells by dipyridamole with a selective increase in fluorodeoxyuridine monophosphate levels. Grem, J.L., Fischer, P.H. Cancer Res. (1986) [Pubmed]
  11. Gremlin gene expression in bovine retinal pericytes exposed to elevated glucose. Kane, R., Stevenson, L., Godson, C., Stitt, A.W., O'Brien, C. The British journal of ophthalmology. (2005) [Pubmed]
  12. Safety assessment of DHA-rich microalgae from Schizochytrium sp. Hammond, B.G., Mayhew, D.A., Naylor, M.W., Ruecker, F.A., Mast, R.W., Sander, W.J. Regulatory toxicology and pharmacology : RTP. (2001) [Pubmed]
  13. Safety assessment of DHA-rich microalgae from Schizochytrium sp. Hammond, B.G., Mayhew, D.A., Kier, L.D., Mast, R.W., Sander, W.J. Regulatory toxicology and pharmacology : RTP. (2002) [Pubmed]
  14. Human cumulus granulosa cell gene expression: a predictor of fertilization and embryo selection in women undergoing IVF. McKenzie, L.J., Pangas, S.A., Carson, S.A., Kovanci, E., Cisneros, P., Buster, J.E., Amato, P., Matzuk, M.M. Hum. Reprod. (2004) [Pubmed]
  15. Lysosomal cathepsins in embryonic programmed cell death. Zuzarte-Luis, V., Montero, J.A., Kawakami, Y., Izpisua-Belmonte, J.C., Hurle, J.M. Dev. Biol. (2007) [Pubmed]
  16. IHG-2, a mesangial cell gene induced by high glucose, is human gremlin. Regulation by extracellular glucose concentration, cyclic mechanical strain, and transforming growth factor-beta1. McMahon, R., Murphy, M., Clarkson, M., Taal, M., Mackenzie, H.S., Godson, C., Martin, F., Brady, H.R. J. Biol. Chem. (2000) [Pubmed]
  17. Unique regulation of SOST, the sclerosteosis gene, by BMPs and steroid hormones in human osteoblasts. Sutherland, M.K., Geoghegan, J.C., Yu, C., Winkler, D.G., Latham, J.A. Bone (2004) [Pubmed]
  18. Gremlin: an example of the re-emergence of developmental programmes in diabetic nephropathy. Lappin, D.W., McMahon, R., Murphy, M., Brady, H.R. Nephrol. Dial. Transplant. (2002) [Pubmed]
  19. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Brunkow, M.E., Gardner, J.C., Van Ness, J., Paeper, B.W., Kovacevich, B.R., Proll, S., Skonier, J.E., Zhao, L., Sabo, P.J., Fu, Y., Alisch, R.S., Gillett, L., Colbert, T., Tacconi, P., Galas, D., Hamersma, H., Beighton, P., Mulligan, J. Am. J. Hum. Genet. (2001) [Pubmed]
  20. Light- and guanosine 5'-3-O-(thio)triphosphate-sensitive localization of a G protein and its effector on detergent-resistant membrane rafts in rod photoreceptor outer segments. Seno, K., Kishimoto, M., Abe, M., Higuchi, Y., Mieda, M., Owada, Y., Yoshiyama, W., Liu, H., Hayashi, F. J. Biol. Chem. (2001) [Pubmed]
  21. The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein. Namkoong, H., Shin, S.M., Kim, H.K., Ha, S.A., Cho, G.W., Hur, S.Y., Kim, T.E., Kim, J.W. BMC Cancer (2006) [Pubmed]
  22. Differential gene expression and regulation of the bone morphogenetic protein antagonists follistatin and gremlin in normal and osteoarthritic human chondrocytes and synovial fibroblasts. Tardif, G., Hum, D., Pelletier, J.P., Boileau, C., Ranger, P., Martel-Pelletier, J. Arthritis Rheum. (2004) [Pubmed]
  23. Bone morphogenetic proteins induce gremlin, a protein that limits their activity in osteoblasts. Pereira, R.C., Economides, A.N., Canalis, E. Endocrinology (2000) [Pubmed]
  24. DRM/GREMLIN (CKTSF1B1) maps to human chromosome 15 and is highly expressed in adult and fetal brain. Topol, L.Z., Modi, W.S., Koochekpour, S., Blair, D.G. Cytogenet. Cell Genet. (2000) [Pubmed]
  25. Spatial segregation of transport and signalling functions between human endothelial caveolae and lipid raft proteomes. Sprenger, R.R., Fontijn, R.D., van Marle, J., Pannekoek, H., Horrevoets, A.J. Biochem. J. (2006) [Pubmed]
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