Ciliary neurotrophic factor

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Ciliary neurotrophic factor
PDB rendering based on 1cnt.
Available structures: 1cnt
Identifiers
Symbol(s) CNTF; HCNTF
External IDs OMIM: 118945 MGI: 88439 HomoloGene: 8288
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 1270 12803
Ensembl ENSG00000205003 n/a
Uniprot P26441 n/a
Refseq NM_000614 (mRNA)
NP_000605 (protein)		 NM_053007 (mRNA)
NP_443733 (protein)
Location Chr 11: 58.15 - 58.15 Mb n/a
Pubmed search [1] [2]

Ciliary neurotrophic factor, also known as CNTF, is a human gene.[1]

The protein encoded by this gene is a polypeptide hormone and nerve growth factor whose actions appear to be restricted to the nervous system where it promotes neurotransmitter synthesis and neurite outgrowth in certain neuronal populations including astrocytes. The protein is a potent survival factor for neurons and oligodendrocytes and may be relevant in reducing tissue destruction during inflammatory attacks. A mutation in this gene, which results in aberrant splicing, leads to ciliary neurotrophic factor deficiency, but this phenotype is not causally related to neurologic disease. In addition to the predominant monocistronic transcript originating from this locus, the gene is also co-transcribed with the upstream ZFP91 gene. Co-transcription from the two loci results in a transcript that contains a complete coding region for the zinc finger protein but lacks a complete coding region for ciliary neurotrophic factor.[1]

Contents

[edit] Satiety effects

In 2001, it was reported that in a human study examining the usefulness of CNTF for treatment of motor neuron disease, CNTF produced an unexpected and substantial weight loss in the study subjects. Further investigation revealed that CNTF could reduce food intake without causing hunger or stress, and is believed to operate by a non-leptin, but 'leptin-like' pathway.[2]

[edit] Axokine

Axokine is a modified version of human Ciliary neurotrophic factor with a 15 amino acid truncation of the C terminus and two amino acid substitutions, which is three to five times more potent than CNTF in in vitro and in vivo assays and has improved stability properties.[3] Like CNTF it is a neurotrophic factor, and may stimulate nerve cells to survive. It was tested in the 1990s as a treatment for amyotrophic lateral sclerosis. It did not improve muscle control as much as expected, but trial participants did report a loss of appetite.

Phase III clinical trials for the drug against obesity were conducted in 2003 by Axokine's maker, Regeneron, demonstrating a small positive effect in some patients, but the drug was not commercialized. According to a March 31, 2003 Regeneron press release [3], a major problem with the treatment was that in nearly 70% of the subjects tested, antibodies against Axokine were produced after approximately three months of treatment. In the minority of subjects who did not develop the antibodies, weight loss averaged 12.5 pounds in one year, versus 4.5 pounds for placebo-treated subjects. In order to obtain this benefit, subjects needed to receive daily subcutaneous injections of one microgram Axokine per kilogram body weight.

Xencor patent application 20050064555 raises the disturbing idea that subjects producing antibodies against CNTF analogues may eventually suffer severe side effects, as these antibodies could potentially interfere with the neuroprotective functions of endogenous CNTF. The application claims methods of designing CNTF analogues with lower immunogenicity than Axokine based on analysis of affinity of each modified epitope for each of 52 class II MHC alleles, and provides specific examples of such modifications. As of November 2006, no such analogues were listed in Xencor's product pipeline.[4]

[edit] See also

[edit] References

  1. ^ a b Entrez Gene: CNTF ciliary neurotrophic factor.
  2. ^ Lambert PD, Anderson KD, Sleeman MW, Wong V, Tan J, Hijarunguru A, Corcoran TL, Murray JD, Thabet KE, Yancopoulos GD, Wiegand SJ (2001). "Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity". Proc. Natl. Acad. Sci. U.S.A. 98 (8): 4652–7. doi:10.1073/pnas.061034298. PMID 11259650. 
  3. ^ Peterson WM, Wang Q, Tzekova R, Wiegand SJ (2000). "Ciliary neurotrophic factor and stress stimuli activate the Jak-STAT pathway in retinal neurons and glia". J. Neurosci. 20 (11): 4081–90. PMID 10818143. 

[edit] Further reading

  • Sendtner M, Carroll P, Holtmann B, et al. (1995). "Ciliary neurotrophic factor.". J. Neurobiol. 25 (11): 1436–53. doi:10.1002/neu.480251110. PMID 7852996. 
  • Sleeman MW, Anderson KD, Lambert PD, et al. (2000). "The ciliary neurotrophic factor and its receptor, CNTFR alpha.". Pharmaceutica acta Helvetiae 74 (2-3): 265–72. PMID 10812968. 
  • Schooltink H, Stoyan T, Roeb E, et al. (1993). "Ciliary neurotrophic factor induces acute-phase protein expression in hepatocytes.". FEBS Lett. 314 (3): 280–4. PMID 1281789. 
  • Bazan JF (1991). "Neuropoietic cytokines in the hematopoietic fold.". Neuron 7 (2): 197–208. PMID 1714745. 
  • Lam A, Fuller F, Miller J, et al. (1991). "Sequence and structural organization of the human gene encoding ciliary neurotrophic factor.". Gene 102 (2): 271–6. PMID 1840538. 
  • Masiakowski P, Liu HX, Radziejewski C, et al. (1991). "Recombinant human and rat ciliary neurotrophic factors.". J. Neurochem. 57 (3): 1003–12. PMID 1861138. 
  • McDonald JR, Ko C, Mismer D, et al. (1991). "Expression and characterization of recombinant human ciliary neurotrophic factor from Escherichia coli.". Biochim. Biophys. Acta 1090 (1): 70–80. PMID 1883844. 
  • Negro A, Tolosano E, Skaper SD, et al. (1991). "Cloning and expression of human ciliary neurotrophic factor.". Eur. J. Biochem. 201 (1): 289–94. PMID 1915374. 
  • Lichter P, Tang CJ, Call K, et al. (1990). "High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones.". Science 247 (4938): 64–9. PMID 2294592. 
  • Winter CG, Saotome Y, Levison SW, Hirsh D (1995). "A role for ciliary neurotrophic factor as an inducer of reactive gliosis, the glial response to central nervous system injury.". Proc. Natl. Acad. Sci. U.S.A. 92 (13): 5865–9. PMID 7597043. 
  • Yokoji H, Ariyama T, Takahashi R, et al. (1995). "cDNA cloning and chromosomal localization of the human ciliary neurotrophic factor gene.". Neurosci. Lett. 185 (3): 175–8. PMID 7753485. 
  • McDonald NQ, Panayotatos N, Hendrickson WA (1995). "Crystal structure of dimeric human ciliary neurotrophic factor determined by MAD phasing.". EMBO J. 14 (12): 2689–99. PMID 7796798. 
  • Saggio I, Paonessa G, Gloaguen I, et al. (1995). "Nonradioactive receptor binding assay for ciliary neurotrophic factor.". Anal. Biochem. 221 (2): 387–91. PMID 7810882. 
  • Takahashi R, Yokoji H, Misawa H, et al. (1994). "A null mutation in the human CNTF gene is not causally related to neurological diseases.". Nat. Genet. 7 (1): 79–84. doi:10.1038/ng0594-79. PMID 8075647. 
  • Giovannini M, Romo AJ, Evans GA (1993). "Chromosomal localization of the human ciliary neurotrophic factor gene (CNTF) to 11q12 by fluorescence in situ hybridization.". Cytogenet. Cell Genet. 63 (1): 62–3. PMID 8449041. 
  • Robledo O, Auguste P, Coupey L, et al. (1996). "Binding interactions of leukemia inhibitory factor and ciliary neurotrophic factor with the different subunits of their high affinity receptors.". J. Neurochem. 66 (4): 1391–9. PMID 8627290. 
  • Gutman CR, Strittmatter WJ, Weisgraber KH, Matthew WD (1997). "Apolipoprotein E binds to and potentiates the biological activity of ciliary neurotrophic factor.". J. Neurosci. 17 (16): 6114–21. PMID 9236223. 
  • Cargill M, Altshuler D, Ireland J, et al. (1999). "Characterization of single-nucleotide polymorphisms in coding regions of human genes.". Nat. Genet. 22 (3): 231–8. doi:10.1038/10290. PMID 10391209. 

[edit] External links

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