Genetic dissection of functional domains within the avian erythroblastosis virus v-erbA oncogene.

Privalsky, Martin L.; Boucher, Philip E.; Koning, A. P. Jason de; Judelson, Catherine

doi:10.1128/mcb.8.10.4510

Cited by 28 publications

(11 citation statements)

References 35 publications

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“…w.t., wild type. bp 543) were wild type in their biochemical and oncogenic properties (8,52) and in their ability to repress both RAR and RXR function in transient transfections (Fig. 8).…”

Section: Methodsmentioning

confidence: 99%

“…8). Insertions in the C-terminal hormone-binding domain dramatically impaired v-ErbA repression of both RXR and RAR activity; these C-terminal mutations have multiple effects on the biochemical and biological properties of the v-ErbA protein and probably disrupt a homo-and heterodimerization domain (8,23,52). Of greatest interest, a small insertion (at bp 92) or base pair change (S61G) in the DNA-binding domain of v-erbA abolished or significantly impaired the ability of the protein to interfere with RAR function without affecting v-ErbA repression of RXR function (Fig.…”

Section: Methodsmentioning

confidence: 99%

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The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms.

Chen¹,

Privalsky²

1993

Mol. Cell. Biol.

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(32,41,60). The corresponding hormone response elements on the DNA consist of repeats of individual hexanucleotide sequences called half-sites (4). Significant overlap exists in the half-site sequences recognized by different receptors; the estrogen, retinoic acid, and thyroid hormone receptors, for example, can all recognize an AG GTCA sequence as a half-site (4). Most known nuclear hormone receptors bind to their cognate response elements as dimers, and the ability of a receptor dimer to recognize a given DNA sequence is influenced by the orientation and spacing, as well as the sequence, of the repeated half-sites that constitute the response element (1, 9, 21-23, 38, 41, 46, 66, 68).Although able to bind DNA as homodimers, the RARs, the T3Rs, and the vitamin D3 receptors are also able to bind DNA as heterodimers, forming complexes with "auxiliary" proteins found in the nuclear extracts of a variety of different cell types (5,6,11,14,26,45,48). Association with these auxiliary proteins results in a higher affinity for the hormone response element in vitro and an enhanced activation of target gene expression in vivo. At least one important class * Corresponding author. of auxiliary proteins, the retinoid X receptors (RXRs), not only serve as heterodimeric partners with the RARs, T3Rs, and vitamin D3 receptors but also are members of the nuclear hormone receptor family in their own right. RXRs regulate gene expression in response to a newly identified retinoid, 9-cis-retinoic acid (34,

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“…w.t., wild type. bp 543) were wild type in their biochemical and oncogenic properties (8,52) and in their ability to repress both RAR and RXR function in transient transfections (Fig. 8).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms.

Chen¹,

Privalsky²

1993

Mol. Cell. Biol.

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“…As in TR␣ and other nuclear hormone receptors such as the glucocorticoid and retinoic acid receptors, v-ErbA has two tandemly repeated zinc finger motifs (Privalsky et al, 1988). Each of these zinc fingers contain four invariant cysteine residues that coordinate with a single zinc ion to form a structure that enables the DNArecognition helix within the first zinc finger to complex with its cis-acting element (Bonde and Privalsky, 1990).…”

Section: V-erba Mutants Failing To Associate With Smad4 Are Unable Tomentioning

confidence: 99%

Association of v-ErbA with Smad4 Disrupts TGF-β Signaling

Erickson

Liu

2009

MBoC

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Disruption of the transforming growth factor-␤ (TGF-␤) pathway is observed in the majority of cancers. To further understand TGF-␤ pathway inactivation in cancer, we stably expressed the v-ErbA oncoprotein in TGF-␤ responsive cells. v-ErbA participates in erythroleukemic transformation of cells induced by the avian erythroblastosis virus (AEV).Here we demonstrate that expression of v-ErbA was sufficient to antagonize TGF-␤-induced cell growth inhibition and that dysregulation of TGF-␤ signaling required that v-ErbA associate with the Smad4 which sequesters Smad4 in the cytoplasm. We also show that AEV-transformed erythroleukemia cells were resistant to TGF-␤-induced growth inhibition and that TGF-␤ sensitivity could be recovered by reducing v-ErbA expression. Our results reveal a novel mechanism for oncogenic disruption of TGF-␤ signaling and provide a mechanistic explanation of v-ErbA activity in AEV-induced erythroleukemia. INTRODUCTIONThe transforming growth factor-␤ (TGF-␤) signaling pathway is a major signaling network that controls cell proliferation, differentiation, and tumor suppression (Massague et al., 2000;Attisano and Wrana, 2002;Wakefield and Roberts, 2002). The TGF-␤ cytokine signals through hetero-oligomeric complexes of type I and type II serine/threonine kinase receptors, TGF-␤ type I (T␤RI) and type II (T␤RII) receptors (Heldin et al., 1997;Massague et al., 2000). On ligand binding to the T␤RII receptor, T␤RII phosphorylates T␤RI and activates the Tß␤RI kinase (Wrana et al., 1992;Chen and Weinberg, 1995). The signal is further propagated by phosphorylation of the downstream signal transducers Smad2 and Smad3 by the type I receptor kinase (Heldin et al., 1997). Phosphorylated Smad2 and Smad3 form a complex with Smad4 and translocate into the nucleus (Massague et al., 2000). These Smad complexes then interact with other transcription factors and bind the promoter regions of TGF-␤-responsive genes to regulate gene expression (Massague et al., 2000).Insensitivity to antigrowth signals such as TGF-␤ is common in cancer cells (Hanahan and Weinberg, 2000;Massague et al., 2000). Multiple genetic mutations are observed in TGF-␤-insensitive tumor cells, and mechanisms have been identified that explain the disruption of TGF-␤'s cytostatic activity. These mechanisms include the down-regulation of TGF-␤ receptors, mutations in TGF-␤ signaling components such as Smad4, and mutations in other downstream targets (Hanahan and Weinberg, 2000;Massague et al., 2000). Overexpression of oncoproteins is also implicated in the disruption of TGF-␤ signaling. Tumor cells insensitive to TGF-␤ are known to overexpress diverse oncoproteins such as Cdk4, Ski, Evi-1, Ras, Mdm2, E6/E7, E1A, and PLZF-RAR␣ (Pietenpol et al., 1990;Ewen et al., 1993;Datto et al., 1997;Kurokawa et al., 1998;Sun et al., 1998;Hanahan and Weinberg, 2000;Massague et al., 2000;La et al., 2003;Luo, 2004). Overexpression of HPV-16 E7 and E1A, for example, is shown to cause TGF-␤ resistance in skin keratinocytes by preventing TGF-␤-induced down-regulatio...

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“…v-ErbA is expressed as a mutated fusion Gag-ErbA protein that has lost its ability to bind T3 but that still binds to specific DNA sequences Abbreviation: AEV, avian erythroblastosis virus; CEF, chicken embryo fibroblast; CHAPS, 3-[(3-cholamidopropyI) dimethylammonio]-1-propane sulfonate; DTE, dithioerythritol; 2-D, two-dimensional; EGF, epidermal growth factor; PAGE, potyacrylamide gel electrophoresis; SDS, sodium dodecyl sulfate; T3, thyroid hormone; TGF, transforming growth factor [13,14]. It functions as a constitutive T3 receptor antagonist by repressing transcription from promoters linked to synthetic or natural T3-response elements [15,16].…”

Section: Introductionmentioning

confidence: 99%

v‐erbB oncogene expression accounts for most variations in protein synthesis after avian erythroblastosis virus infection of chicken embryo fibroblasts: A two‐dimensional electrophoresis study

et al. 1992

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The effect of the v-erbA and/or v-erbB oncogenes on cellular gene expression was investigated after separation by two-dimensional polyacrylamide gel electrophoresis of [35S]methionine-labelled proteins from chicken embryo fibroblasts (CEF), infected by either the avian erythroblastosis virus (AEV) carrying both oncogenes, or by viruses carrying only one of them. We observed significant changes in the synthesis of 34 proteins in AEV-transformed CEF as compared with control cells. The synthesis of 24 of them was increased while the synthesis of the other 10 proteins was decreased. The expression of v-erbB alone is necessary and sufficient to induce changes in the synthesis of 27 proteins while the 7 remaining modifications are observed only in cells expressing v-erbB together with v-erbA. Moreover, the deregulation of protein synthesis by v-erbB-expressing viruses was correlated with the morphological transformation state of cells.

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Genetic dissection of functional domains within the avian erythroblastosis virus v-erbA oncogene.

Cited by 28 publications

References 35 publications

The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms.

The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms.

Association of v-ErbA with Smad4 Disrupts TGF-β Signaling

v‐erbB oncogene expression accounts for most variations in protein synthesis after avian erythroblastosis virus infection of chicken embryo fibroblasts: A two‐dimensional electrophoresis study

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