Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of the c-erbB-2/HER2 protooncogene in breast carcinoma is controlled not only by the degree of amplification of the gene but also at the level of gene transcription. Thus, whether or not the gene is amplified, the activity of the c-erbB-2 promoter is enhanced in overexpressing cells through the binding of an additional transcription factor, OB2-1, whose activity is increased in these lines. Here we describe further characterization of OB2-1 and show that it is identical to the developmentally regulated transcription factor AP-2. Functional assays confirm that AP-2 is able to regulate c-erbB-2 expression in mammary-derived cell lines. Furthermore, although AP-2 is barely detectable in cells with the low c-erbB-2 expression phenotype, protein levels are clearly elevated in a panel of c-erbB-2-overexpressing lines. These findings demonstrate an important role for this transcription factor in human cancer.
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PMID:The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma. 784 46

The retinoic acid-inducible transcription factor AP-2 is expressed in epithelial and neural crest cell lineages during murine development. AP-2 can regulate neural and epithelial gene transcription, and is associated with overexpression of c-erbB-2 in human breast-cancer cell lines. To ascertain the importance of AP-2 for normal development, we have derived mice containing a homozygous disruption of the AP-2 gene. These AP-2-null mice have multiple congenital defects and die at birth. In particular, the AP-2 knockout mice exhibit anencephaly, craniofacial defects and thoraco-abdominoschisis. Skeletal defects occur in the head and trunk region, where many bones are deformed or absent. Analysis of these mice earlier in embryogenesis indicates a failure of cranial neural-tube closure and defects in cranial ganglia development. We have shown that AP-2 is a fundamental regulator of mammalian craniofacial development.
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PMID:Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. 862 66

The proto-oncogene c-erbB-2 is overexpressed in 25-30% of breast cancers through increased transcription and amplification of the gene. We have previously described a factor, OB2-1 which upregulates c-erbB-2 transcription and which is closely related to the developmentally regulated transcription factor, AP-2. Further analysis of affinity purified OB2-1 has now shown that it is in fact a combination of proteins from three AP-2-related genes, the previously described AP-2alpha gene and two new human family members, AP-2beta and AP-2gamma whose cloning and characterisation are described here. All three AP-2 proteins show a high degree of homology and are capable of binding to the c-erbB-2 promoter as homo- or heterodimers. The three proteins can also activate a c-erbB-2 reporter construct, but AP-2alpha and AP-2gamma are 3-4 times more active in this regard than AP-2beta. In addition both AP-2alpha and AP-2gamma are expressed at elevated levels in the majority of c-erbB-2 overexpressing mammary tumour lines examined. Mechanisms which may have led to the increased AP-2 levels in these cells are discussed.
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PMID:A family of AP-2 proteins regulates c-erbB-2 expression in mammary carcinoma. 889 16

The AP-2 transcription factors are required for normal growth and morphogenesis during mammalian development. Previous in vitro studies have also indicated that the AP-2 family of proteins may be involved in the etiology of human breast cancer. The AP-2 genes are expressed in many human breast cancer cell lines, and critical AP-2-binding sites are present in both the ERBB-2 (HER2/neu) and estrogen receptor promoters. We have now characterized immunological reagents that enable specific AP-2 family members, including AP-2alpha and AP-2gamma, to be detected in human breast cancer epithelium. Data obtained with these reagents demonstrate that whereas AP-2alpha and AP-2gamma are both present in benign breast epithelia, there is a significant up-regulation of AP-2gamma expression in breast cancer specimens (P = 0.01). There was also a significant correlation between the presence of the AP-2alpha protein and estrogen receptor expression (P = 0.018) and between specimens containing both AP-2alpha/AP-2gamma proteins and ERBB-2 expression (P = 0.003). Furthermore, we detected an association (P = 0.04) between the expression of AP-2gamma and the presence of an additional signal transduction molecule implicated in breast cancer, the insulin-like growth factor I receptor. Analysis of the proximal promoter of the insulin-like growth factor I receptor revealed a novel AP-2-binding site. Thus, AP-2 proteins may directly regulate the transcription of this growth factor receptor. Taken together, these data strongly support a role for the AP-2 gene family in the control of cell growth and differentiation in breast cancer.
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PMID:Expression of AP-2 transcription factors in human breast cancer correlates with the regulation of multiple growth factor signalling pathways. 985 80

The AP-2 family of transcription factors consists of three known members, namely AP-2alpha, AP-2beta, and AP-2gamma. In experimental systems AP-2 factors possess tumor suppressor-like activities, and alterations in the AP-2 expression pattern have been described for some tumor entities. In addition, AP-2 has been implicated in the transcriptional control of human papillomaviruses (HPVs). We investigated here the expression pattern of AP-2alpha, AP-2beta, and AP-2gamma, as well as that of the cellular AP-2 target gene c-erbB-2, in a series of cervical cancer cell lines. In addition, we analyzed the influence of AP-2 factors on the activity of the HPV16 and HPV18 E6/E7 oncogene promoter. We found that, with the exception of HPV-negative C33A cells, all investigated cervical cancer cell lines expressed all three AP-2 family members, although at varying levels. No linear correlation between AP-2 and c-erbB-2 levels was observed. Although AP-2alpha, AP-2beta, and AP-2gamma can activate the c-erbB-2 promoter in reporter gene assays, they do not stimulate the HPV16 or HPV18 E6/E7 promoter. These results indicate that, although a rare event, loss of AP-2 expression occurs in cervical cancer cells. Moreover, AP-2alpha, AP-2beta, and AP-2gamma are neither sufficient nor required to activate the viral E6/E7 promoter.
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PMID:Expression pattern of AP-2 transcription factors in cervical cancer cells and analysis of their influence on human papillomavirus oncogene transcription. 1148 26

A causative role of the membrane-bound tyrosine kinase ErbB-2 in breast tumorigenesis has been well established. MMTV/neu transgenic mice which overexpress ErbB-2 consistently develop mammary carcinomas with a high incidence. In human breast cancer, ErbB-2 is overexpressed in 25-30 of all cases and is representing a clinical marker of a poor prognosis. Besides to gene amplification, ErbB-2 overexpression has been attributed to transcription factors of the AP-2 family which were shown to control the ErbB-2 gene promoter in cell culture studies. Particularly AP-2alpha and gamma are often coexpressed in ErbB-2-positive breast carcinomas. However, LTRgamma transgenic mice which overexpress AP-2gamma in their mammary epithelium display only a very weak upregulation of the erbB-2 gene and do not develop mammary carcinoma. These findings therefore raise the possibility of functional cooperativity between both genes in breast cancer. To experimentally address the impact of AP-2gammaon ErbB-2-induced breast carcinogenesis we crossed MMTV/neu transgenic mice with LTRgamma transgenic mice and monitored tumor development in bitransgenic female progeny. AP-2gamma overexpression negatively influenced tumor incidence, as reflected by a reduced tumor number and a prolonged tumor latency. Histological analysis revealed three major types of tumors corresponding to different stages of tumor progression. Interestingly, an increased proportion of advanced stage carcinomas was observed in bitransgenic mice. Moreover, the AP-2gamma transgene differentially affected proliferation rates between the different progression stages: proliferation was enhanced at early stages but reduced in advanced stages in comparison to control tumors. Therefore, AP-2gamma while reducing the incidence of mammary tumors is promoting tumor progression.
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PMID:Dual role of AP-2gamma in ErbB-2-induced mammary tumorigenesis. 1583 Jan 41

HER-2/neu proto-oncogene is overexpressed in about one fourth of human breast cancers. AP-2 transcription factors bind to the HER-2/neu gene promoter and activate its expression. In a striking concurrence, anomalous abundance of AP-2alpha protein or its homolog AP-2gamma is also detected with HER-2/neu protein in mammary tumor-derived cell lines. This suggests that the deregulation of AP-2 is the preceding pathogenic event and probably the pivotal one in this type of mammary carcinogenesis. We examined the process of AP-2alpha gene expression in mammary carcinoma cell lines to identify where the aberration had occurred. We found no amplification of the AP-2alpha gene. Its promoter was marginally upregulated; however, it did not significantly increase the mRNA levels. When the AP-2alpha protein was examined, a remarkable stability was seen in breast cancer cell lines MDA-MB-453 and SK-BR-3, with a half-life of over 30 hr. This is sharply higher than the approximate 1 hr observed in mammary epithelial cell line MCF-10A and murine cell line NIH 3T3. Treatment of MCF-10A and NIH 3T3 cells with the proteasome inhibitor MG-132 showed that AP-2alpha was ubiquitinated and its level significantly increased. Moreover, this increase was accompanied by elevated levels HER-2/neu protein. In contrast, weaker ubiquitination of AP-2alpha was seen in MDA-MB-453 and SK-BR-3 cancer cells, and MG-132 treatment did not raise the AP-2alpha level any further. These results uncover that unusual stability is the main mechanism that raises the levels of AP-2 proteins, and in addition, provide the first clue that defective ubiquitin-dependent proteasomal-degradation pathway is possibly the prime cause that affects the HER-2/neu gene and culminates in breast cancer.
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PMID:Inefficient proteasomal-degradation pathway stabilizes AP-2alpha and activates HER-2/neu gene in breast cancer. 1610 32