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Gene Review

NAE1  -  NEDD8 activating enzyme E1 subunit 1

Homo sapiens

Synonyms: A-116A10.1, APP-BP1, APPBP1, Amyloid beta precursor protein-binding protein 1, 59 kDa, Amyloid protein-binding protein 1, ...
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Disease relevance of APPBP1

  • This mini-review focuses on how the amyloid precursor protein (APP) plays a central role in AD and Down syndrome as the regulator of the APP-BP1/hUba3 activated neddylation pathway [1].
  • We identified the protooncogene and guanine nucleotide exchange factor Vav as the specific binding partner of Nef proteins from HIV-1 and SIV [2].
  • These results demonstrate that the phenotype of B lineage lymphomas induced by MYC dysregulation is highly dependent on cooperativity among the regulatory elements that govern expression of the protooncogene and provide a new system for studying the pathogenesis of BL [3].
  • We report that a disease with striking similarities to human mastocytosis develops spontaneously in transgenic mice expressing the human Asp816Val mutant Kit protooncogene specifically in MCs [4].
  • When mitogen was used to activate the B cells in vitro, their pattern of protooncogene expression changed to resemble that found in freshly isolated cells from lupus patients [5].

Psychiatry related information on APPBP1


High impact information on APPBP1

  • One component of human telomeres is the TTAGGG repeat binding factor 1 (TRF1), a ubiquitously expressed protein, related to the protooncogene Myb, that is present at telomeres throughout the cell cycle [8].
  • The highly polymorphic HRAS1 minisatellite locus just downstream from the protooncogene H-ras-1 consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors [9].
  • Alveolar macrophages constitutively express low levels of c-sis, the protooncogene coding for the B chain of platelet-derived growth factor, a protein with chemotactic and mitogenic activity toward mesenchymal cells [10].
  • Therefore, both pRB and p53 can be subjected to negative regulation by the product of a single cellular protooncogene [11].
  • The c-abl protooncogene is translocated from chromosome 9 band q34 into bcr and the biochemical consequence of this molecular rearrangement is the production of an abnormal fusion protein bcr-abl p210 with enhanced protein-tyrosine kinase activity compared to the normal p145 c-abl protein [12].

Chemical compound and disease context of APPBP1


Biological context of APPBP1


Anatomical context of APPBP1


Associations of APPBP1 with chemical compounds

  • Transfection with the antiapoptotic protooncogene Bcl-2 simultaneously inhibits mitochondrial alterations and apoptotic cell death triggered by steroids or ceramide [25].
  • In vitro estrogen responses in osteoclasts included a dose-dependent decrease in resorption as well as an increase in nuclear protooncogene mRNA levels [26].
  • One of these tyrosine-phosphorylated proteins had an apparent molecular mass of 95 kDa and was identified as the protooncogene product Vav, a p21ras guanine nucleotide exchange factor that is specifically expressed in cells of hematopoietic lineage [27].
  • The protooncogene c-myb encodes a nuclear transcription factor that binds to DNA in a sequence-specific manner and transactivates transcription of several viral and cellular genes [28].
  • Protooncogene c-fos is induced by activation of adenylate cyclase through the major cAMP-responsive element (CRE) centered at position -60 of the promoter. cAMP induction is followed by a rapid decrease in transcriptional rate, reminiscent of down-regulation after serum stimulation [29].

Physical interactions of APPBP1

  • APP-BP1 binds to the amyloid precursor protein (APP) carboxyl-terminal domain [18].
  • The neurotrophic activities of GDNF are mediated by binding to GFRalpha1 and further interaction of the GDNF-GFRalpha1 complex with a coreceptor tyrosine kinase encoded by the c-Ret protooncogene [30].
  • p210BCR/ABL induces formation of complexes containing focal adhesion proteins and the protooncogene product p120c-Cbl [31].
  • The Myc promoter-binding protein-1 (MBP-1) is a 37-38 kDa protein that binds to the c-myc P2 promoter and negatively regulates transcription of the protooncogene [32].
  • These findings indicate, for the first time, that the BK receptor is coupled to the important protooncogene c-src and that the src pathway may mediate some of the events downstream from BK binding [33].

Enzymatic interactions of APPBP1


Regulatory relationships of APPBP1


Other interactions of APPBP1

  • Not surprisingly, mutations in APPBP1 and UBA3 lead to defects in many cellular functions [39].
  • Recent work suggests that APP-BP1 participates in a novel ubiquitinylation-related pathway involving the ubiquitin-like molecule NEDD8 [18].
  • The coexpression of a potent mitogenic growth factor protooncogene (c-sis) and its receptor gene in astrocytoma tumor cells suggests the presence of an autocrine mechanism that may contribute to the development and maintenance of astrocytomas [40].
  • The protein product of the neu protooncogene, p185c-neu, is structurally similar to the epidermal growth factor receptor (EGFR) [41].
  • The Ser/Thr kinase Raf-1 is a protooncogene product that is a central component in many signaling pathways involved in normal cell growth and oncogenic transformation [42].

Analytical, diagnostic and therapeutic context of APPBP1


  1. APP induces neuronal apoptosis through APP-BP1-mediated downregulation of beta-catenin. Chen, Y.Z. Apoptosis (2004) [Pubmed]
  2. Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions. Fackler, O.T., Luo, W., Geyer, M., Alberts, A.S., Peterlin, B.M. Mol. Cell (1999) [Pubmed]
  3. Burkitt lymphoma in the mouse. Kovalchuk, A.L., Qi, C.F., Torrey, T.A., Taddesse-Heath, L., Feigenbaum, L., Park, S.S., Gerbitz, A., Klobeck, G., Hoertnagel, K., Polack, A., Bornkamm, G.W., Janz, S., Morse, H.C. J. Exp. Med. (2000) [Pubmed]
  4. Mastocytosis in mice expressing human Kit receptor with the activating Asp816Val mutation. Zappulla, J.P., Dubreuil, P., Desbois, S., Létard, S., Hamouda, N.B., Daëron, M., Delsol, G., Arock, M., Liblau, R.S. J. Exp. Med. (2005) [Pubmed]
  5. Oncogene expression in autoimmune and normal peripheral blood mononuclear cells. Klinman, D.M., Mushinski, J.F., Honda, M., Ishigatsubo, Y., Mountz, J.D., Raveche, E.S., Steinberg, A.D. J. Exp. Med. (1986) [Pubmed]
  6. APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is increased in Alzheimer's disease brain. Chen, Y., Liu, W., McPhie, D.L., Hassinger, L., Neve, R.L. J. Cell Biol. (2003) [Pubmed]
  7. Expression of c-Fos-like immunoreactivity in the brain of mice with learned helplessness. Huang, Y.H., Cheng, C.Y., Hong, C.J., Tsai, S.J. Neurosci. Lett. (2004) [Pubmed]
  8. Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Broccoli, D., Smogorzewska, A., Chong, L., de Lange, T. Nat. Genet. (1997) [Pubmed]
  9. An association between the risk of cancer and mutations in the HRAS1 minisatellite locus. Krontiris, T.G., Devlin, B., Karp, D.D., Robert, N.J., Risch, N. N. Engl. J. Med. (1993) [Pubmed]
  10. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. Martinet, Y., Rom, W.N., Grotendorst, G.R., Martin, G.R., Crystal, R.G. N. Engl. J. Med. (1987) [Pubmed]
  11. Interaction between the retinoblastoma protein and the oncoprotein MDM2. Xiao, Z.X., Chen, J., Levine, A.J., Modjtahedi, N., Xing, J., Sellers, W.R., Livingston, D.M. Nature (1995) [Pubmed]
  12. A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia. Chan, L.C., Karhi, K.K., Rayter, S.I., Heisterkamp, N., Eridani, S., Powles, R., Lawler, S.D., Groffen, J., Foulkes, J.G., Greaves, M.F. Nature (1987) [Pubmed]
  13. Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners. Vähäkangas, K.H., Samet, J.M., Metcalf, R.A., Welsh, J.A., Bennett, W.P., Lane, D.P., Harris, C.C. Lancet (1992) [Pubmed]
  14. Astrocyte apoptosis induced by HIV-1 transactivation of the c-kit protooncogene. He, J., deCastro, C.M., Vandenbark, G.R., Busciglio, J., Gabuzda, D. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  15. Suppression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake. Hurwitz, E., Stancovski, I., Sela, M., Yarden, Y. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  16. TPR-MET oncogenic rearrangement: detection by polymerase chain reaction amplification of the transcript and expression in human tumor cell lines. Soman, N.R., Wogan, G.N., Rhim, J.S. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  17. Effects of steroid hormones and peptide growth factors on protooncogene c-fos expression in human breast cancer cells. Wilding, G., Lippman, M.E., Gelmann, E.P. Cancer Res. (1988) [Pubmed]
  18. The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons. Chen, Y., McPhie, D.L., Hirschberg, J., Neve, R.L. J. Biol. Chem. (2000) [Pubmed]
  19. Amplification and enhanced expression of the epidermal growth factor receptor gene in A431 human carcinoma cells. Merlino, G.T., Xu, Y.H., Ishii, S., Clark, A.J., Semba, K., Toyoshima, K., Yamamoto, T., Pastan, I. Science (1984) [Pubmed]
  20. Mouse tumor model for neurofibromatosis type 1. Vogel, K.S., Klesse, L.J., Velasco-Miguel, S., Meyers, K., Rushing, E.J., Parada, L.F. Science (1999) [Pubmed]
  21. The protein product of the c-cbl protooncogene is phosphorylated after B cell receptor stimulation and binds the SH3 domain of Bruton's tyrosine kinase. Cory, G.O., Lovering, R.C., Hinshelwood, S., MacCarthy-Morrogh, L., Levinsky, R.J., Kinnon, C. J. Exp. Med. (1995) [Pubmed]
  22. Deregulated Syk inhibits differentiation and induces growth factor-independent proliferation of pre-B cells. Wossning, T., Herzog, S., K??hler, F., Meixlsperger, S., Kulathu, Y., Mittler, G., Abe, A., Fuchs, U., Borkhardt, A., Jumaa, H. J. Exp. Med. (2006) [Pubmed]
  23. Inhibition of c-fes expression by an antisense oligomer causes apoptosis of HL60 cells induced to granulocytic differentiation. Manfredini, R., Grande, A., Tagliafico, E., Barbieri, D., Zucchini, P., Citro, G., Zupi, G., Franceschi, C., Torelli, U., Ferrari, S. J. Exp. Med. (1993) [Pubmed]
  24. Expression of c-fos protooncogene in normal human peripheral blood granulocytes. Colotta, F., Wang, J.M., Polentarutti, N., Mantovani, A. J. Exp. Med. (1987) [Pubmed]
  25. Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. Zamzami, N., Marchetti, P., Castedo, M., Decaudin, D., Macho, A., Hirsch, T., Susin, S.A., Petit, P.X., Mignotte, B., Kroemer, G. J. Exp. Med. (1995) [Pubmed]
  26. Avian osteoclasts as estrogen target cells. Oursler, M.J., Osdoby, P., Pyfferoen, J., Riggs, B.L., Spelsberg, T.C. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  27. Antibody-induced engagement of beta 2 integrins on adherent human neutrophils triggers activation of p21ras through tyrosine phosphorylation of the protooncogene product Vav. Zheng, L., Sjölander, A., Eckerdal, J., Andersson, T. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  28. Myb protein binds to human immunodeficiency virus 1 long terminal repeat (LTR) sequences and transactivates LTR-mediated transcription. Dasgupta, P., Saikumar, P., Reddy, C.D., Reddy, E.P. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  29. Transcriptional antagonist cAMP-responsive element modulator (CREM) down-regulates c-fos cAMP-induced expression. Foulkes, N.S., Laoide, B.M., Schlotter, F., Sassone-Corsi, P. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  30. Internalization of glial cell-derived neurotrophic factor receptor GFR alpha 1 in the absence of the ret tyrosine kinase coreceptor. Vieira, P., Thomas-Crusells, J., Vieira, A. Cell. Mol. Neurobiol. (2003) [Pubmed]
  31. p210BCR/ABL induces formation of complexes containing focal adhesion proteins and the protooncogene product p120c-Cbl. Salgia, R., Sattler, M., Pisick, E., Li, J.L., Griffin, J.D. Exp. Hematol. (1996) [Pubmed]
  32. ENO1 gene product binds to the c-myc promoter and acts as a transcriptional repressor: relationship with Myc promoter-binding protein 1 (MBP-1). Feo, S., Arcuri, D., Piddini, E., Passantino, R., Giallongo, A. FEBS Lett. (2000) [Pubmed]
  33. Tyrosine phosphorylation and activation of pp60c-src and pp125FAK in bradykinin-stimulated fibroblasts. Lee, K.M., Villereal, M.L. Am. J. Physiol. (1996) [Pubmed]
  34. Codons 12 and 13 of H-ras protooncogene interrupt the progression of DNA synthesis catalyzed by DNA polymerase alpha. Hoffmann, J.S., Fry, M., Ji, J., Williams, K.J., Loeb, L.A. Cancer Res. (1993) [Pubmed]
  35. Interferon-alpha-induced gene expression: evidence for a selective effect of ouabain on activation of the ISGF3 transcription complex. Nakagawa, Y., Petricoin, E.F., Akai, H., Grimley, P.M., Rupp, B., Larner, A.C. Virology (1992) [Pubmed]
  36. IFN-gamma activates the C3G/Rap1 signaling pathway. Alsayed, Y., Uddin, S., Ahmad, S., Majchrzak, B., Druker, B.J., Fish, E.N., Platanias, L.C. J. Immunol. (2000) [Pubmed]
  37. Cellular protoonocogenes are infrequently amplified in untreated non-small cell lung cancer. Slebos, R.J., Evers, S.G., Wagenaar, S.S., Rodenhuis, S. Br. J. Cancer (1989) [Pubmed]
  38. Complete sequencing of the murine USF gene and comparison of its genomic organization to that of mFIP/USF2. Aperlo, C., Boulukos, K.E., Sage, J., Cuzin, F., Pognonec, P. Genomics (1996) [Pubmed]
  39. Expression, purification, and characterization of the E1 for human NEDD8, the heterodimeric APPBP1-UBA3 complex. Huang, D.T., Schulman, B.A. Meth. Enzymol. (2005) [Pubmed]
  40. Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance. Maxwell, M., Naber, S.P., Wolfe, H.J., Galanopoulos, T., Hedley-Whyte, E.T., Black, P.M., Antoniades, H.N. J. Clin. Invest. (1990) [Pubmed]
  41. p185c-neu and epidermal growth factor receptor associate into a structure composed of activated kinases. Quian, X.L., Decker, S.J., Greene, M.I. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  42. Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Chen, J., Fujii, K., Zhang, L., Roberts, T., Fu, H. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  43. Bone marrow-derived osteoclast-like cells from a patient with craniometaphyseal dysplasia lack expression of osteoclast-reactive vacuolar proton pump. Yamamoto, T., Kurihara, N., Yamaoka, K., Ozono, K., Okada, M., Yamamoto, K., Matsumoto, S., Michigami, T., Ono, J., Okada, S. J. Clin. Invest. (1993) [Pubmed]
  44. Quantitation of Harvey ras p21 enhanced expression in human breast and colon carcinomas. Hand, P.H., Vilasi, V., Thor, A., Ohuchi, N., Schlom, J. J. Natl. Cancer Inst. (1987) [Pubmed]
  45. Isolation and chromosomal localization of the human fgr protooncogene, a distinct member of the tyrosine kinase gene family. Tronick, S.R., Popescu, N.C., Cheah, M.S., Swan, D.C., Amsbaugh, S.C., Lengel, C.R., DiPaolo, J.A., Robbins, K.C. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  46. Nucleotide sequence of the human N-myc gene. Stanton, L.W., Schwab, M., Bishop, J.M. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
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