Alpha-fetoprotein

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Alpha-fetoprotein
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols AFP ; FETA; HPAFP
External IDs OMIM104150 MGI87951 HomoloGene36278 GeneCards: AFP Gene
RNA expression pattern
PBB GE AFP 204694 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 174 11576
Ensembl ENSG00000081051 ENSMUSG00000054932
UniProt P02771 P02772
RefSeq (mRNA) NM_001134 NM_007423
RefSeq (protein) NP_001125 NP_031449
Location (UCSC) Chr 4:
74.3 – 74.32 Mb
Chr 5:
90.49 – 90.51 Mb
PubMed search [1] [2]

Alpha-fetoprotein (AFP, α-fetoprotein; also sometimes called alpha-1-fetoprotein, alpha-fetoglobulin, or alpha fetal protein) is a protein[1][2] that in humans is encoded by the AFP gene.[3][4] The AFP gene is located on the q arm of chromosome 4 (4q25).

AFP is a major plasma protein produced by the yolk sac and the liver during fetal development. It is thought to be the fetal form of serum albumin. AFP binds to copper, nickel, fatty acids and bilirubin[4] and is found in monomeric, dimeric and trimeric forms.

Structure[edit]

AFP is a glycoprotein of 591 amino acids[5] and a carbohydrate moiety.[6]

Function[edit]

AFP is the most abundant plasma protein found in the human fetus. Plasma levels decrease rapidly after birth but begin decreasing prenatally starting at the end of the first trimester. Normal adult levels are usually achieved by the age of 8 to 12 months. The function of AFP in adult humans is unknown; however, in rodents it binds estradiol to prevent the transport of this hormone across the placenta to the fetus. The main function of this is to prevent the virilization of female fetuses. As human AFP does not bind estrogen, its function in humans is less clear.[7]

The rodent AFP system can be overridden with massive injections of estrogen, which overwhelm the AFP system and will masculinize the fetus. The masculinizing effect of estrogens may seem counter-intuitive since estrogens are critical for the proper development of female secondary characteristics during puberty. However, this is not the case prenatally. Gonadal hormones from the testes, such as testosterone and antimullerian hormone are required to cause development of a phenotypic male. Without these hormones the fetus will develop into a phenotypic female even if genetically XY. Interestingly, the conversion of testosterone into estradiol by aromatase in many tissues may be an important step in masculinization of that tissue.[8][9] Masculinization of the brain is thought to occur both by conversion of testosterone into estradiol by aromatase, but also by de novo synthesis of estrogens within the brain.[10][11] Thus, AFP may protect the fetus from maternal estradiol that would otherwise have a masculinizing effect on the fetus, but its exact role is still controversial.

Serum levels[edit]

Maternal[edit]

In pregnant women, fetal AFP levels can be monitored in urine. AFP is cleared strongly from the kidneys allowing AFP to tend to mirror fetal serum levels. In contrast, maternal serum AFP levels are much lower but continue to rise until about week 32. This is thought to be because the mother is not utilising the AFP, and therefore clears it from her system without issue.

Infants[edit]

The normal range of AFP for adults and children is variously reported as under 50, under 10, and under 5 ng/mL.[12][13] At birth, normal infants have AFP levels 4 or more orders of magnitude above this normal range, that decreases to a normal range over the first year of life.[14][15][16][17][18][19]

During this time, the normal range of AFP levels spans approximately 2 orders of magnitude.[16] Correct evaluation of abnormal AFP levels in infants must take into account these normal patterns.[16]

Very high AFP levels may be subject to hooking (see Tumor marker), which results in the level being reported significantly lower than the actual concentration.[20] This is important for analysis of a series of AFP tumor marker tests, e.g. in the context of post-treatment early surveillance of cancer survivors, where the rate of decrease of AFP has diagnostic value.

Clinical significance[edit]

AFP is measured in pregnant women through the analysis of maternal blood or amniotic fluid, as a screening test for a subset of developmental abnormalities. Some of the diseases in which AFP will be elevated in a person are listed below:

  • Omphalocele[21][22]
  • Hepatocellular carcinoma/hepatoma: ↑ α-fetoprotein[23]
  • Neural tube defects: ↑ α-fetoprotein in amniotic fluid and maternal serum[23][24]
  • Nonseminomatous germ cell tumors
  • Yolk sac tumor[23]
  • Ataxia telangiectasia: Elevation of AFP is used as one factor in the diagnosis of ataxia telangiectasia.[25]
  • Tumors: AFP can also be used as a biomarker to detect a subset of tumors in non-pregnant women, men, and children. A level above 500 nanograms/milliliter of AFP in adults can be indicative of hepatocellular carcinoma, germ cell tumors, and metastatic cancers of the liver.

A peptide derived from AFP that is referred to as AFPep is claimed to possess anti-cancer properties.[26]

See also[edit]

References[edit]

  1. ^ Tomasi TB (1977). "Structure and function of alpha-fetoprotein". Annual review of medicine 28: 453–65. doi:10.1146/annurev.me.28.020177.002321. PMID 67821. 
  2. ^ Mizejewski GJ (May 2001). "Alpha-fetoprotein structure and function: relevance to isoforms, epitopes, and conformational variants". Experimental Biology and Medicine 226 (5): 377–408. PMID 11393167. 
  3. ^ Harper ME, Dugaiczyk A (July 1983). "Linkage of the evolutionarily-related serum albumin and alpha-fetoprotein genes within q11-22 of human chromosome 4". American Journal of Human Genetics 35 (4): 565–72. PMC 1685723. PMID 6192711. 
  4. ^ a b "Entrez Gene: Alpha-fetoprotein". 
  5. ^ Pucci P, Siciliano R, Malorni A, Marino G, Tecce MF, Ceccarini C, Terrana B (May 1991). "Human alpha-fetoprotein primary structure: a mass spectrometric study". Biochemistry 30 (20): 5061–6. doi:10.1021/bi00234a032. PMID 1709810. 
  6. ^ Seregni E, Botti C, Bombardieri E (1995). "Biochemical characteristics and clinical applications of alpha-fetoprotein isoforms". Anticancer Res. 15 (4): 1491–9. PMID 7544570. 
  7. ^ Carter CS (2002). "Neuroendocrinology of sexual behavior in the female". In Becker JB. Behavioral Endocrinology. Cambridge, Mass: MIT Press. pp. 88–89. ISBN 0-262-52321-3. 
  8. ^ Nef S, Parada LF (December 2000). "Hormones in male sexual development". Genes Dev. 14 (24): 3075–86. doi:10.1101/gad.843800. PMID 11124800. 
  9. ^ Elbrecht A, Smith RG (1992). "Aromatase enzyme activity and sex determination in chickens.". Science 255 (5043): 467–70. doi:10.1126/science.1734525. PMID 1734525. 
  10. ^ Bakker J, Baum MJ (2008). "Role for estradiol in female-typical brain and behavioral sexual differentiation.". Front Neuroendocrinol 29 (1): 1–16. doi:10.1016/j.yfrne.2007.06.001. PMC 2373265. PMID 17720235. 
  11. ^ Harding CF (2004). "Hormonal modulation of singing: hormonal modulation of the songbird brain and singing behavior.". Annals of the New York Academy of Sciences 1016: 524–39. doi:10.1196/annals.1298.030. PMID 15313793. 
  12. ^ Ball D, Rose E, Alpert E (March 1992). "Alpha-fetoprotein levels in normal adults". Am. J. Med. Sci. 303 (3): 157–9. doi:10.1097/00000441-199203000-00004. PMID 1375809. 
  13. ^ Sizaret P, Martel N, Tuyns A, Reynaud S (February 1977). "Mean alpha-fetoprotein values of 1,333 males over 15 years by age groups". Digestion 15 (2): 97–103. doi:10.1159/000197990. PMID 65304. 
  14. ^ Blohm ME, Vesterling-Hörner D, Calaminus G, Göbel U (1998). "Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age". Pediatr Hematol Oncol 15 (2): 135–42. doi:10.3109/08880019809167228. PMID 9592840. 
  15. ^ Ohama K, Nagase H, Ogino K, Tsuchida K, Tanaka M, Kubo M, Horita S, Kawakami K, Ohmori M (October 1997). "Alpha-fetoprotein (AFP) levels in normal children". Eur J Pediatr Surg 7 (5): 267–9. doi:10.1055/s-2008-1071168. PMID 9402482. 
  16. ^ a b c Lee PI, Chang MH, Chen DS, Lee CY (January 1989). "Serum alpha-fetoprotein levels in normal infants: a reappraisal of regression analysis and sex difference". J. Pediatr. Gastroenterol. Nutr. 8 (1): 19–25. doi:10.1097/00005176-198901000-00005. PMID 2471821. 
  17. ^ Blair JI, Carachi R, Gupta R, Sim FG, McAllister EJ, Weston R (April 1987). "Plasma alpha fetoprotein reference ranges in infancy: effect of prematurity". Arch. Dis. Child. 62 (4): 362–9. doi:10.1136/adc.62.4.362. PMC 1778344. PMID 2439023. 
  18. ^ Bader D, Riskin A, Vafsi O, Tamir A, Peskin B, Israel N, Merksamer R, Dar H, David M (November 2004). "Alpha-fetoprotein in the early neonatal period--a large study and review of the literature". Clin. Chim. Acta 349 (1-2): 15–23. doi:10.1016/j.cccn.2004.06.020. PMID 15469851. 
  19. ^ Wu JT, Roan Y, Knight JA (1985). "Serum levels of AFP in normal infants: their clinical and physiological significance". In Mizejewski GJ, Porter I. Alfa-Fetoprotein and Congenital Disorders. New York: Academic Press. pp. 111–122. 
  20. ^ Jassam N, Jones CM, Briscoe T, Horner JH (July 2006). "The hook effect: a need for constant vigilance". Ann. Clin. Biochem. 43 (Pt 4): 314–7. doi:10.1258/000456306777695726. PMID 16824284. 
  21. ^ Szabó M, Veress L, Münnich A, Papp Z (September 1990). "[Alpha fetoprotein concentration in the amniotic fluid in normal pregnancy and in pregnancy complicated by fetal anomaly]". Orv Hetil (in Hungarian) 131 (39): 2139–42. PMID 1699194. 
  22. ^ Rosen T, D'Alton ME (December 2005). "Down syndrome screening in the first and second trimesters: what do the data show?". Semin. Perinatol. 29 (6): 367–75. doi:10.1053/j.semperi.2006.01.001. PMID 16533649. 
  23. ^ a b c Le, Tao. First Aid for the USMLE Step 1 2013. New York: McGraw-Hill Medical, 2013. Print.
  24. ^ Bredaki FE, Poon LC, Birdir C, Escalante D, Nicolaides KH (2012). "First-trimester screening for neural tube defects using alpha-fetoprotein". Fetal. Diagn. Ther. 31 (2): 109–14. doi:10.1159/000335677. PMID 22377693. 
  25. ^ Taylor AM, Byrd PJ (October 2005). "Molecular pathology of ataxia telangiectasia". J. Clin. Pathol. 58 (10): 1009–15. doi:10.1136/jcp.2005.026062. PMC 1770730. PMID 16189143. 
  26. ^ Mesfin FB, Bennett JA, Jacobson HI, Zhu S, Andersen TT (April 2000). "Alpha-fetoprotein-derived antiestrotrophic octapeptide". Biochimica et Biophysica Acta 1501 (1): 33–43. doi:10.1016/S0925-4439(00)00008-9. PMID 10727847. 

Further reading[edit]

  • Nahon JL (1987). "The regulation of albumin and alpha-fetoprotein gene expression in mammals". Biochimie 69 (5): 445–59. doi:10.1016/0300-9084(87)90082-4. PMID 2445387. 
  • Tilghman SM (1989). "The structure and regulation of the alpha-fetoprotein and albumin genes". Oxf. Surv. Eukaryot. Genes 2: 160–206. PMID 2474300. 
  • Mizejewski GJ (2003). "Biological role of alpha-fetoprotein in cancer: prospects for anticancer therapy". Expert Rev Anticancer Ther 2 (6): 709–35. doi:10.1586/14737140.2.6.709. PMID 12503217. 
  • Yachnin S, Hsu R, Heinrikson RL, Miller JB (1977). "Studies on human alpha-fetoprotein. Isolation and characterization of monomeric and polymeric forms and amino-terminal sequence analysis". Biochim. Biophys. Acta 493 (2): 418–28. PMID 70228. 
  • Aoyagi Y, Ikenaka T, Ichida F (1977). "Comparative chemical structures of human alpha-fetoproteins from fetal serum and from ascites fluid of a patient with hepatoma". Cancer Res. 37 (10): 3663–7. PMID 71198. 
  • Aoyagi Y, Ikenaka T, Ichida F (1978). "Copper(II)-binding ability of human alpha-fetoprotein". Cancer Res. 38 (10): 3483–6. PMID 80265. 
  • Aoyagi Y, Ikenaka T, Ichida F (1979). "alpha-Fetoprotein as a carrier protein in plasma and its bilirubin-binding ability". Cancer Res. 39 (9): 3571–4. PMID 89900. 
  • Torres JM, Anel A, Uriel J (1992). "Alpha-fetoprotein-mediated uptake of fatty acids by human T lymphocytes". J. Cell. Physiol. 150 (3): 456–62. doi:10.1002/jcp.1041500305. PMID 1371512. 
  • Greenberg F, Faucett A, Rose E, et al. (1992). "Congenital deficiency of alpha-fetoprotein". Am. J. Obstet. Gynecol. 167 (2): 509–11. PMID 1379776. 
  • Bansal V, Kumari K, Dixit A, Sahib MK (1991). "Interaction of human alpha fetoprotein with bilirubin". Indian J. Exp. Biol. 28 (7): 697–8. PMID 1703124. 
  • Pucci P, Siciliano R, Malorni A, et al. (1991). "Human alpha-fetoprotein primary structure: a mass spectrometric study". Biochemistry 30 (20): 5061–6. doi:10.1021/bi00234a032. PMID 1709810. 
  • Liu MC, Yu S, Sy J, et al. (1985). "Tyrosine sulfation of proteins from the human hepatoma cell line HepG2". Proceedings of the National Academy of Sciences of the United States of America 82 (21): 7160–4. doi:10.1073/pnas.82.21.7160. PMC 390808. PMID 2414772. 
  • Gibbs PE, Zielinski R, Boyd C, Dugaiczyk A (1987). "Structure, polymorphism, and novel repeated DNA elements revealed by a complete sequence of the human alpha-fetoprotein gene". Biochemistry 26 (5): 1332–43. doi:10.1021/bi00379a020. PMID 2436661. 
  • Sakai M, Morinaga T, Urano Y, et al. (1985). "The human alpha-fetoprotein gene. Sequence organization and the 5' flanking region". J. Biol. Chem. 260 (8): 5055–60. PMID 2580830. 
  • Ruoslahti E, Pihko H, Vaheri A, et al. (1975). "Alpha fetoprotein: structure and expression in man and inbred mouse strains under normal conditions and liver injury". Johns Hopkins Med. J. Suppl. 3: 249–55. PMID 4138095. 
  • Urano Y, Sakai M, Watanabe K, Tamaoki T (1985). "Tandem arrangement of the albumin and alpha-fetoprotein genes in the human genome". Gene 32 (3): 255–61. doi:10.1016/0378-1119(84)90001-5. PMID 6085063. 
  • Beattie WG, Dugaiczyk A (1983). "Structure and evolution of human alpha-fetoprotein deduced from partial sequence of cloned cDNA". Gene 20 (3): 415–22. doi:10.1016/0378-1119(82)90210-4. PMID 6187626. 
  • Morinaga T, Sakai M, Wegmann TG, Tamaoki T (1983). "Primary structures of human alpha-fetoprotein and its mRNA". Proceedings of the National Academy of Sciences of the United States of America 80 (15): 4604–8. doi:10.1073/pnas.80.15.4604. PMC 384092. PMID 6192439. 

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.