Epidermal growth factor induced tyrosine phosphorylation of nuclear proteins associated with translocation of epidermal growth factor receptor into the nucleus

Holt, S.J.; Alexander, Peter; Inman, C.B.E.; Davies, Donna E.

doi:10.1016/0006-2952(94)90444-8

Cited by 43 publications

(51 citation statements)

References 33 publications

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“…274 Epidermal growth factor was also found to relocate to the nucleus, after binding of its ligand. 275,276 Such observations are often made when proteins affected by genetic changes in hematologic neoplasia alter their subcellular localization (Table 5), and it is frequently concluded that the sites to which proteins relocate must be the sites of their oncogenic action. However, the NPM-ALK chimeric protein, for example, despite its prominent nuclear (and, in particular, nucleolar) localization, almost certainly exerts its lymphomagenic effect within the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry

Falini

Mason

2002

Blood

176

147

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IntroductionTranslocations, deletions, and other nonrandom chromosomal abnormalities 1,2 play a central role in the pathogenesis of many human hematologic malignant diseases. A growing number of studies are revealing the ways in which these chromosomal alterations affect specific genes, such as those encoding nuclear transcription factors. However, any gene implicated in the neoplastic process can act only through the protein it encodes. Many of the consequences of chromosomal changes with respect to abnormal protein expression have been inferred indirectly by analysis of messenger RNA (mRNA) transcription, but it is clear that protein and mRNA levels do not always correlate. For example, germinalcenter B cells appear to contain BCL-2 message but little protein, 3,4 and the same is true for TAL-1 in erythroid cells. 5 Many examples of the opposite combination (high protein and little or no message) also exist, such as BCL-2 in mature lymphocytes 6,7 and elastase in mature myeloid cells. 8 Antibody-based detection of the protein is therefore required, but this frequently cannot be done because of a lack of suitable reagents. Consequently, we are often ignorant not only about patterns of expression of oncogenic proteins in hematologic neoplasms but also about possible abnormalities in the distribution and subcellular localization of these proteins.Most of the currently recognized genetic alterations in human leukemias and lymphomas result in either activation of a quiescent gene or creation of a hybrid gene encoding a chimeric protein. Table 1 summarizes the genetic abnormalities that have been studied using antibodies specific for the protein products of genes involved in such rearrangements. We here review the immunocytochemical studies that have been done with these antibodies and assess, for each protein, whether abnormalities demonstrable by immunocytochemistry are of clinical value in determining diagnosis or predicting prognosis. Immunocytochemical findings that are of value are discussed below, whereas those for which no clear clinical applications have been observed are described briefly in Table 2. Genes activated by chromosomal changesThe CCND1 (BCL-1) gene and its protein product (cyclin D1) CCND1 (BCL-1) gene. The (11;14)(q13;q32) translocation, 9 an anomaly often found in mantle cell (centrocytic) lymphoma 10,11 and occasionally in other B-cell neoplasms, notably myeloma, 12,13 From For personal use only. on May 12, 2018. by guest www.bloodjournal.org From juxtaposes the CCND1 (BCL-1) locus encoding cyclin D1 on chromosome 11 to an immunoglobulin-enhancer sequence on chromosome 14. 9 The CCND1 gene is transcriptionally silent in normal lymphohemopoietic tissues 14,15 ; thus, expression of the protein may promote neoplastic cell proliferation by perpetuating the transition from G 1 to S. 16 Antibodies to cyclin D1. Several antibodies recognizing cyclin D1 have been described (Table 3), [14][15][16][17][18] but hematopathologists know that immunocytochemical detection of cyclin D1 in routinely processe...

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Section: Discussionmentioning

confidence: 99%

Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry

Falini

Mason

2002

Blood

176

147

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“…Using a variety of techniques, other transmembrane receptors have been shown to be translocated to the nucleus upon stimulation by the ligands. These include insulin receptors (Podlecki et al, 1987), epidermal growth factor receptors (Rakowicz-Szulczynska et al, 1989;Jiang and Schindler, 1990;Marti et al,1991;Holt et al, 1994), HER2 (Xie and Hung, 1994) and IL-1 receptors (Curtis et al, 1990). Similar experiments can be done on nuclei preparation from female mouse kidneys to con®rm the nuclear localization of RET and to identify other protein(s) which may bind to RET and directs its intracellular localization.…”

Section: Discussionmentioning

confidence: 99%

Sex difference in immunostaining of RET in the adult mouse kidney

Chan

Lee

1998

Oncogene

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“…That the nucleus is an important site of direct action on the part of EGFR is supported by studies showing that exogenously added EGF can stimulate autophosphorylation of the EGFR, along with stimulation of phosphorylation of other non-EGF-binding proteins in isolated nuclei and nuclear membranes (Holt et al, 1994). Further, use of monoclonal antibody directed against the extracellular domain of EGFR inhibited the phosphorylation induced by EGF in isolated nuclei (Holt et al, 1994;Cao et al, 1995).…”

Section: Nuclear Substrates Of Egfrmentioning

confidence: 98%

“…The same studies demonstrated that the nuclear membranes and isolated chromatin contained EGFR which was indistinguishable from plasma membrane localized EGFR both biochemically and immunologically (Rakowicz-Szulczynska et al, 1989;Oksvold et al, 2002;Cao et al, 1995;Marti et al, 1991;Marti and Wells, 2000). Further, EGF could stimulate phosphorylation of nuclear EGFR and other nuclear proteins in isolated nuclei and nuclear membranes, and could be specifically inhibited by monoclonal antibodies directed against the extracellular domain of cell surface EGFR (Holt et al, 1994). In normal tissues, nuclear expression of EGFR has been shown to be associated with the acquisition of proliferative capabilities of the cell.…”

Section: Nuclear Localization and Functionmentioning

confidence: 99%

“…Further, use of monoclonal antibody directed against the extracellular domain of EGFR inhibited the phosphorylation induced by EGF in isolated nuclei (Holt et al, 1994;Cao et al, 1995). Thus, apart from functioning as a transcriptional coregulator to modulate gene expression, the regulated kinase activity of EGFR in the nucleus can control the activation state of nuclear factors and thereby gene expression as well as other functions of such nuclear factors.…”

Section: Nuclear Substrates Of Egfrmentioning

confidence: 99%

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