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

• A similar increase in APP-BP1 in lipid rafts is observed in the Alzheimer's disease brain hippocampus, but not in less-affected areas of Alzheimer's disease brain [6].
• The learned helplessness (LH) developed after repeat inescapable stress is a well validated animal model of human major depression and is not species specific. c-Fos, the protein product of the protooncogene c-fos, is expressed in neurons under a variety of stressors and could reflect the regional neuronal activation [7].

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

• To investigate the mutational spectrum associated with exposure to high levels of radon, we sequenced exons 5-9 of the p53 tumour suppressor gene and codons 12-13 of the Ki-ras protooncogene in 19 lung cancers from uranium miners exposed to radon and tobacco smoke [13].
• We report herein that HIV-1 infection of primary brain cultures induces the receptor tyrosine kinase protooncogene c-kit and that high levels of c-Kit expression are associated with astrocyte apoptosis [14].
• Amplification and overexpression of the erbB-2/neu protooncogene are frequently associated with aggressive clinical course of certain human adenocarcinomas, and therefore the encoded surface glycoprotein is considered a candidate target for immunotherapy [15].
• Activation of the MET protooncogene by a rearrangement involving the fusion of TPR and MET specific gene sequences has been observed in a human osteosarcoma cell line (HOS) treated in vitro with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) [16].
• To investigate if the estrogen control of the tumorigenic phenotype of breast cancer cells was mediated through activation of the c-fos protooncogene, we examined the expression of this oncogene in MCF-7 cells [17].

Biological context of APPBP1

• We have shown that APP-BP1 drives the S- to M-phase transition in dividing cells, and causes apoptosis in neurons [6].
• APP-BP1, first identified as an amyloid precursor protein (APP) binding protein, is the regulatory subunit of the activating enzyme for the small ubiquitin-like protein NEDD8 [6].
• The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons [18].
• The sequence of the human epidermal growth factor (EGF) receptor shows great homology with the avian erythroblastosis virus v-erb B oncogene, raising the possibility that the receptor gene is identical to the c-erb B protooncogene [19].
• Mutations that activate the protooncogene ras, such as loss of Nf1, cooperate with inactivating mutations at the p53 tumor suppressor gene during malignant transformation [20].

Anatomical context of APPBP1

• We have shown that this 120-kD protein is the protein product of c-cbl, a protooncogene, which is known to be phosphorylated in response to T cell receptor stimulation and to interact with several other tyrosine kinases [21].
• Collectively, our data suggest that Syk is a protooncogene involved in the transformation of lymphocytes, thus making Syk a potential target for the treatment of leukemia [22].
• To tackle this problem, the c-fes protooncogene expression has been inhibited in HL60 cells, and fresh leukemic promyelocytes of acute promyelocytic leukemia have been induced to differentiate with retinoic acid (RA) and dimethylsulfoxide (DMSO) [23].
• Expression of c-fos protooncogene in normal human peripheral blood granulocytes [24].
• These data indicate that the myelomonocytic differentiation pathway c-fos expression is not peculiar to monocytes/macrophages and that PMN may represent a suitable system with which to investigate the link between protooncogene expression and functional activation [24].

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

• 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 [21].
• Codons 12 and 13 of H-ras protooncogene interrupt the progression of DNA synthesis catalyzed by DNA polymerase alpha [34].

Regulatory relationships of APPBP1

• APP induces neuronal apoptosis through APP-BP1-mediated downregulation of beta-catenin [1].
• Ouabain itself induced RNA of the protooncogene c-fos which conversely was inhibited by IFN-alpha [35].
• We report that IFN-gamma activates a distinct signaling cascade involving the c-cbl protooncogene product, CrkL adapter, and small G protein Rap1 [36].
• None of the tumours with an amplified protooncogene simultaneously harboured a mutationally activated K-ras gene [37].
• USF is a transcription factor able to stimulate promoter activity upon binding to an upstream sequence identical to that recognized by the protooncogene Myc [38].

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

• We have investigated by Northern blot analysis the expression of c-fos protooncogene in human peripheral blood polymorphonuclear leukocytes (PMN) [24].
• Western blot analysis using a monoclonal antibody to pp60c-src (327) revealed that protooncogene c-src expression by the platelets of the CMD patient was comparable to the normal control [43].
• With the use of a direct-binding liquid competition radioimmunoassay (RIA), capable of providing truly quantitative analysis of the 21,000-dalton (p21) ras oncogene and protooncogene products, absolute levels of Ha-ras p21 have been determined in human breast and colon carcinomas, benign lesions, and/or their respective normal tissues [44].
• In addition, the fgr protooncogene was localized to the distal portion of the short arm of human chromosome 1 at p36.1-36.2 by in situ hybridization [45].
• It has therefore been proposed that N-myc is itself a protooncogene, and subsequent tests have shown that N-myc and c-myc have similar biological activities in cell culture [46].

References