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Thomas D Gilmore - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Oncogenic Transcription Factor Rel by the Natural Product Derivative Calafianin Monomer 101 Induces Proliferation Arrest and Apoptosis in Human B-Lymphoma Cell Lines
Molecules (Basel Switzerland), 2015Co-Authors: Alan T. Yeo, John A. Porco, Spandan Chennamadhavuni, Adrian Whitty, Thomas D GilmoreAbstract:Increased activity of Transcription Factor NF-κB has been implicated in many B-cell lymphomas. We investigated effects of synthetic compound calafianin monomer (CM101) on biochemical and biological properties of NF-κB. In human 293 cells, CM101 selectively inhibited DNA binding by overexpressed NF-κB subunits Rel (human c-Rel) and p65 as compared to NF-κB p50, and inhibition of Rel and p65 DNA binding by CM101 required a conserved cysteine residue. CM101 also inhibited DNA binding by Rel in human B-lymphoma cell lines, and the sensitivity of several B-lymphoma cell lines to CM101-induced proliferation arrest and apoptosis corRelated with levels of cellular and nuclear Rel. CM101 treatment induced both phosphorylation and decreased expression of anti-apoptotic protein Bcl-XL, a Rel target gene product, in sensitive B-lymphoma cell lines. Ectopic expression of Bcl-XL protected SUDHL-2 B-lymphoma cells against CM101-induced apoptosis, and overexpression of a transforming mutant of Rel decreased the sensitivity of BJAB B-lymphoma cells to CM101-induced apoptosis. Lipopolysaccharide-induced activation of NF-κB signaling upstream components occurred in RAW264.7 macrophages at CM101 concentrations that blocked NF-κB DNA binding. Direct inhibitors of Rel may be useful for treating B-cell lymphomas in which Rel is active, and may inhibit B-lymphoma cell growth at doses that do not affect some immune-Related responses in normal cells.
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Histone acetyltransferase-deficient p300 mutants in diffuse large B cell lymphoma have altered Transcriptional regulatory activities and are required for optimal cell growth
Molecular Cancer, 2014Co-Authors: Leila Haery, Julián G Lugo-picó, Ryan A Henry, Andrew J Andrews, Thomas D GilmoreAbstract:Background Recent genome-wide studies have shown that approximately 30% of diffuse large B-cell lymphoma (DLBCL) cases harbor mutations in the histone acetyltransferase (HAT) coactivators p300 or CBP. The majority of these mutations reduce or eliminate the catalytic HAT activity. We previously demonstrated that the human DLBCL cell line RC-K8 expresses a C-terminally truncated, HAT-defective p300 protein (p300ΔC-1087), whose expression is essential for cell proliferation. Methods Using results from large-scale DLBCL studies, we have identified and characterized a second C-terminally truncated, HAT-defective p300 mutant, p300ΔC-820, expressed in the SUDHL2 DLBCL cell line. Properties of p300ΔC-820 were characterized in the SUDHL2 DLBCL cell line by Western blotting, co-immunoprecipitation, and shRNA gene knockdown, as well by using cDNA expression vectors for p300ΔC-820 in pull-down assays, Transcriptional reporter assays, and immunofluorescence experiments. A mass spectrometry-based method was used to compare the histone acetylation profile of DLBCL cell lines expressing various levels of wild-type p300. Results We show that the SUDHL2 cell line expresses a C-terminally truncated, HAT-defective form of p300 (p300ΔC-820), but no wild-type p300. The p300ΔC-820 protein has a wild-type ability to localize to subnuclear “speckles,” but has a reduced ability to enhance transactivation by Transcription Factor Rel. Knockdown of p300ΔC-820 in SUDHL2 cells reduced their proliferation and soft agar colony-forming ability. In RC-K8 cells, knockdown of p300ΔC-1087 resulted in increased expression of mRNA and protein for Rel target genes A20 and IκBα, two genes that have been shown to limit the growth of RC-K8 cells when overexpressed. Among a panel of B-lymphoma cell lines, low-level expression of full-length p300 protein, which is characteristic of the SUDHL2 and RC-K8 cells, was associated with decreased acetylation of histone H3 at lysines 14 and 18. Conclusions The high prevalence of p300 mutations in DLBCL suggests that HAT-deficient p300 activity defines a subtype of DLBCL, which we have investigated using human DLBCL cell lines RC-K8 and SUDHL2. Our results suggest that truncated p300 proteins contribute to DLBCL cell growth by affecting the expression of specific genes, perhaps through a mechanism that involves alterations in global histone acetylation.
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a rearranged ep300 gene in the human b cell lymphoma cell line rc k8 encodes a disabled Transcriptional co activator that contributes to cell growth and oncogenicity
Cancer Letters, 2011Co-Authors: Michael R Garbati, Ryan C Thompson, Leila Haery, Thomas D GilmoreAbstract:Human diffuse large B-cell lymphoma cell line RC-K8 has an altered EP300 locus that encodes a C-terminally truncated histone acetyltransferase (HAT) protein (p300ΔC). We now show that p300ΔC contains 1047 N-terminal amino acids of p300 fused to 25 amino acids encoded by sequences from chromosome 6. Over-expressed p300ΔC localized to nuclear subdomains and interacted with Transcription Factor Rel. p300ΔC did not function as a co-activator for Rel-directed transactivation, and blocked the ability of wild-type p300 to enhance Transcriptional activation by Rel. Knock down of p300ΔC in RC-K8 cells reduced their growth in both liquid culture and soft agar. Truncations of p300 were not found in eight other B-lymphoma cell lines. These results suggest that p300ΔC contributes to the oncogenic state of RC-K8 cells by acting as a defective co-activator.
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Histone acetyltransferase p300 is a coactivator for Transcription Factor Rel and is C-terminally truncated in the human diffuse large B-cell lymphoma cell line RC-K8
Cancer letters, 2009Co-Authors: Michael R Garbati, Gökçen Alço, Thomas D GilmoreAbstract:Abstract Human c-Rel (Rel) is a member of the NF-κB family of Transcription Factors. Rel’s normal physiological role is in the regulation of B-cell proliferation and survival. The Rel gene is amplified in many human B-cell lymphomas and overexpression of Rel can transform chicken lymphoid cells. In this report, histone acetyltransferase p300 enhanced Rel-induced transactivation and interacted with Rel both in vitro and in Rel-transformed chicken spleen cells and the B-lymphoma cell line RC-K8, in which Rel is constitutively active and required for proliferation. However, due to a deletion in the EP300 locus, only a C-terminally truncated form of p300 is expressed in RC-K8 cells. These results suggest a role for p300 in Rel-mediated oncogenic activity in B lymphoma.
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The synthetic epoxyquinoids jesterone dimer and epoxyquinone A monomer induce apoptosis and inhibit Rel (human c-Rel) DNA binding in an IκBα-deficient diffuse large B-cell lymphoma cell line
Cancer letters, 2005Co-Authors: Mei-chih Liang, Sujata Bardhan, John A. Porco, Thomas D GilmoreAbstract:Abstract The NF-κB Transcription Factor signaling pathway is constitutively active in many human cancers, and inhibition of this pathway can often kill cancer cells by inducing apoptosis. In this study, we show that two synthetic epoxyquinoids, jesterone dimer (JD) and epoxyquinone A monomer (EqM), are equally effective at inhibiting the growth of two human lymphoma cell lines that have constitutively nuclear Rel (human c-Rel) DNA-binding complexes, but either express (SUDHL-4 cells) or do not express (RC-K8 cells) the NF-κB inhibitor IκBα. Furthermore, in these cells, both JD and EqM dose-dependently induced apoptosis, inhibited Rel DNA-binding activity, and converted Rel to a high molecular weight form. In A293 cells, JD and EqM inhibited the DNA-binding activity of overexpressed Rel, but not p50. Replacement of Cys-27 with Ser in Rel reduced JD- and EqM-mediated inhibition of Rel DNA-binding activity. These results suggest that JD and EqM can induce apoptosis in IκBα-deficient lymphoma cells through a mechanism involving direct inhibition of Transcription Factor Rel.
Daniel T Starczynowski - One of the best experts on this subject based on the ideXlab platform.
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Mutations of tumor necrosis Factor α-responsive serine residues within the C-terminal transactivation domain of human Transcription Factor Rel enhance its in vitro transforming ability
Oncogene, 2005Co-Authors: Daniel T Starczynowski, Joseph G Reynolds, Thomas D GilmoreAbstract:The human c- Rel gene ( Rel ), encoding an NF- κ B Transcription Factor, is amplified or mutated in several human B-cell lymphomas and can transform chicken lymphoid cells in vitro . We have previously shown that certain deletions of C-terminal transactivation sequences enhance Rel's transforming ability in chicken spleen cells. In this report, we have analysed the effect of single amino-acid changes at select serine residues in the C-terminal transactivation domain on Rel's transforming ability. Mutation of either of two TNF α -inducible serine residues (Ser460 and Ser471) to nonphosphorylatable residues (alanine, asparagine, phenylalanine) made Rel more efficient at transforming chicken spleen cells in vitro . In contrast, mutation of Ser471 to a phosphorylation mimetic aspartate residue impaired Rel's transforming ability, even though it increased Rel's inherent transactivation ability as a GAL4-fusion protein. Alanine mutations of several other serine residues within the transactivation domain did not substantially affect Rel's transforming ability. Transactivation by GAL4-Rel fusion proteins containing either transformation enhancing or nonenhancing mutations at serine residues was generally similar to wild-type GAL4-Rel. However, more transforming mutants with mutations at either Ser460 or Ser471 differed from wild-type Rel in their ability to transactivate certain κ B-site reporter genes. In particular, the SOD2 promoter, encoding manganese superoxide dismutase, was activated less strongly by the more transforming Rel mutant Rel-S471N in transient assays, but Rel-S471N-transformed chicken spleen cells had increased levels of MnSOD protein as compared to wild-type Rel-transformed cells. Taken together, our results show that mutations of certain serine residues can enhance Rel's transforming ability in vitro and suggest that these mutations increase Rel-mediated transformation by altering Rel's ability to modulate the expression of select target genes. Furthermore, phosphorylation of Ser471 may be involved in Rel-mediated modulation of transformation-specific target gene expression. Lastly, these results suggest that similar mutations in the Rel transactivation domain contribute to the development of certain human B-cell lymphomas.
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Mutations of tumor necrosis Factor alpha-responsive serine residues within the C-terminal transactivation domain of human Transcription Factor Rel enhance its in vitro transforming ability.
Oncogene, 2005Co-Authors: Daniel T Starczynowski, Joseph G Reynolds, Thomas D GilmoreAbstract:The human c-Rel gene (Rel), encoding an NF-κB Transcription Factor, is amplified or mutated in several human B-cell lymphomas and can transform chicken lymphoid cells in vitro. We have previously shown that certain deletions of C-terminal transactivation sequences enhance Rel's transforming ability in chicken spleen cells. In this report, we have analysed the effect of single amino-acid changes at select serine residues in the C-terminal transactivation domain on Rel's transforming ability. Mutation of either of two TNFα-inducible serine residues (Ser460 and Ser471) to nonphosphorylatable residues (alanine, asparagine, phenylalanine) made Rel more efficient at transforming chicken spleen cells in vitro. In contrast, mutation of Ser471 to a phosphorylation mimetic aspartate residue impaired Rel's transforming ability, even though it increased Rel's inherent transactivation ability as a GAL4-fusion protein. Alanine mutations of several other serine residues within the transactivation domain did not substantially affect Rel's transforming ability. Transactivation by GAL4-Rel fusion proteins containing either transformation enhancing or nonenhancing mutations at serine residues was generally similar to wild-type GAL4-Rel. However, more transforming mutants with mutations at either Ser460 or Ser471 differed from wild-type Rel in their ability to transactivate certain κB-site reporter genes. In particular, the SOD2 promoter, encoding manganese superoxide dismutase, was activated less strongly by the more transforming Rel mutant Rel-S471N in transient assays, but Rel-S471N-transformed chicken spleen cells had increased levels of MnSOD protein as compared to wild-type Rel-transformed cells. Taken together, our results show that mutations of certain serine residues can enhance Rel's transforming ability in vitro and suggest that these mutations increase Rel-mediated transformation by altering Rel's ability to modulate the expression of select target genes. Furthermore, phosphorylation of Ser471 may be involved in Rel-mediated modulation of transformation-specific target gene expression. Lastly, these results suggest that similar mutations in the Rel transactivation domain contribute to the development of certain human B-cell lymphomas.
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Deletion of either C-terminal transactivation subdomain enhances the in vitro transforming activity of human Transcription Factor Rel in chicken spleen cells
Oncogene, 2003Co-Authors: Daniel T Starczynowski, Joseph G Reynolds, Thomas D GilmoreAbstract:The Rel gene is amplified in many human B-cell lymphomas and we have previously shown that expression of Rel from a retroviral vector can malignantly transform chicken spleen cells in vitro . To identify Rel protein functions necessary for malignant transformation, we have performed deletion analysis on Rel sequences encoding residues of two C-terminal subdomains that are involved in Transcriptional activation. We find that deletion of both C-terminal transactivation subdomains abolishes the ability of Rel to transform chicken spleen cells in vitro . In contrast, deletion of either transactivation subdomain alone, which reduces the transactivation ability of Rel, enhances the transforming activity of Rel. Transforming Rel mutants missing C-terminal sequences can also be selected at a low frequency in vitro . The Rel transactivation domain can be functionally replaced in transformation assays by a portion of the VP16 transactivation domain that activates at a level similar to Rel-transforming mutants. We also find that deletion of 29 C-terminal amino acids causes the subcellular localization of Rel to change from cytoplasmic to nuclear in chicken embryo fibroblasts. In contrast, wild-type Rel and all transforming Rel mutants are located primarily in the cytoplasm of transformed spleen cells. Nevertheless, treatment of transformed spleen cells with leptomycin B causes wild-type Rel and two Rel mutants to Relocalize to the nucleus, and nuclear extracts from these transformed cells contain Rel DNA-binding activity. Taken together, these results suggest the following: (1) that Rel must activate Transcription to transform cells in vitro ; (2) that a reduced level of transactivation enhances the oncogenicity of Rel; (3) that Rel shuttles from the cytoplasm to the nucleus in transformed chicken spleen cells; and (4) that mutations in Rel , in addition to amplifications, could activate its oncogenicity in human lymphomas.
Rongqing Zhang - One of the best experts on this subject based on the ideXlab platform.
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Pf-Rel, a Rel/Nuclear Factor-κB Homolog Identified from the Pearl Oyster, Pinctada fucata
2014Co-Authors: Xunhao Xiong, Liping Xie, Rongqing ZhangAbstract:Abstract Transcription Factor Rel/nuclear Factor-kappa B (NF-κB) has been the focus of many studies since its discovery in 1986. Different homologs of Rel/NF-κB have been found in both vertebrate and invertebrate. A cDNA clone encoding a putative Rel/NF-κB homolog (designated Pf-Rel) was isolated from the pearl oyster, Pinctada fucata. The sequence of Pf-Rel consists of the Rel homology domain, IPT NF-κB domain and C-terminal transactivation domain. Sequence analysis of Pf-Rel shows that it shares high similarity with other Rel/NF-κB family proteins, especially within the conserved domains. Reverse Transcription-polymerase chain reaction analysis revealed that Pf-Rel mRNA was expressed ubiquitously. Further in situ hybridization analysis showed that Pf-Rel mRNA was expressed mainly at the outer epithelial cells of the middle fold and the inner epithelial cells of the outer fold. The identification and characterization of pearl oyster Pf-Rel help to further investigate the involvement of Rel/NF-κB in oyster immunity and other biological processes
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Pf‐Rel, a Rel/Nuclear Factor‐κB Homolog Identified from the Pearl Oyster, Pinctada fucata
Acta biochimica et biophysica Sinica, 2007Co-Authors: Xunhao Xiong, Liping Xie, Rongqing ZhangAbstract:Transcription Factor Rel/nuclear Factor-kappa B (NF-κB) has been the focus of many studies since its discovery in 1986. Different homologs of Rel/NF-κB have been found in both vertebrate and invertebrate. A cDNA clone encoding a putative Rel/NF-κB homolog (designated Pf-Rel) was isolated from the pearl oyster, Pinctada fucata. The sequence of Pf-Rel consists of the Rel homology domain, IPT NF-κB domain and C-terminal transactivation domain. Sequence analysis of Pf-Rel shows that it shares high similarity with other Rel/NF-κB family proteins, especially within the conserved domains. Reverse Transcription-polymerase chain reaction analysis revealed that Pf-Rel mRNA was expressed ubiquitously. Further in situ hybridization analysis showed that Pf-Rel mRNA was expressed mainly at the outer epithelial cells of the middle fold and the inner epithelial cells of the outer fold. The identification and characterization of pearl oyster Pf-Rel help to further investigate the involvement of Rel/NF-κB in oyster immunity and other biological processes.
Michael R Garbati - One of the best experts on this subject based on the ideXlab platform.
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a rearranged ep300 gene in the human b cell lymphoma cell line rc k8 encodes a disabled Transcriptional co activator that contributes to cell growth and oncogenicity
Cancer Letters, 2011Co-Authors: Michael R Garbati, Ryan C Thompson, Leila Haery, Thomas D GilmoreAbstract:Human diffuse large B-cell lymphoma cell line RC-K8 has an altered EP300 locus that encodes a C-terminally truncated histone acetyltransferase (HAT) protein (p300ΔC). We now show that p300ΔC contains 1047 N-terminal amino acids of p300 fused to 25 amino acids encoded by sequences from chromosome 6. Over-expressed p300ΔC localized to nuclear subdomains and interacted with Transcription Factor Rel. p300ΔC did not function as a co-activator for Rel-directed transactivation, and blocked the ability of wild-type p300 to enhance Transcriptional activation by Rel. Knock down of p300ΔC in RC-K8 cells reduced their growth in both liquid culture and soft agar. Truncations of p300 were not found in eight other B-lymphoma cell lines. These results suggest that p300ΔC contributes to the oncogenic state of RC-K8 cells by acting as a defective co-activator.
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Histone acetyltransferase p300 is a coactivator for Transcription Factor Rel and is C-terminally truncated in the human diffuse large B-cell lymphoma cell line RC-K8
Cancer letters, 2009Co-Authors: Michael R Garbati, Gökçen Alço, Thomas D GilmoreAbstract:Abstract Human c-Rel (Rel) is a member of the NF-κB family of Transcription Factors. Rel’s normal physiological role is in the regulation of B-cell proliferation and survival. The Rel gene is amplified in many human B-cell lymphomas and overexpression of Rel can transform chicken lymphoid cells. In this report, histone acetyltransferase p300 enhanced Rel-induced transactivation and interacted with Rel both in vitro and in Rel-transformed chicken spleen cells and the B-lymphoma cell line RC-K8, in which Rel is constitutively active and required for proliferation. However, due to a deletion in the EP300 locus, only a C-terminally truncated form of p300 is expressed in RC-K8 cells. These results suggest a role for p300 in Rel-mediated oncogenic activity in B lymphoma.
Joseph G Reynolds - One of the best experts on this subject based on the ideXlab platform.
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Mutations of tumor necrosis Factor α-responsive serine residues within the C-terminal transactivation domain of human Transcription Factor Rel enhance its in vitro transforming ability
Oncogene, 2005Co-Authors: Daniel T Starczynowski, Joseph G Reynolds, Thomas D GilmoreAbstract:The human c- Rel gene ( Rel ), encoding an NF- κ B Transcription Factor, is amplified or mutated in several human B-cell lymphomas and can transform chicken lymphoid cells in vitro . We have previously shown that certain deletions of C-terminal transactivation sequences enhance Rel's transforming ability in chicken spleen cells. In this report, we have analysed the effect of single amino-acid changes at select serine residues in the C-terminal transactivation domain on Rel's transforming ability. Mutation of either of two TNF α -inducible serine residues (Ser460 and Ser471) to nonphosphorylatable residues (alanine, asparagine, phenylalanine) made Rel more efficient at transforming chicken spleen cells in vitro . In contrast, mutation of Ser471 to a phosphorylation mimetic aspartate residue impaired Rel's transforming ability, even though it increased Rel's inherent transactivation ability as a GAL4-fusion protein. Alanine mutations of several other serine residues within the transactivation domain did not substantially affect Rel's transforming ability. Transactivation by GAL4-Rel fusion proteins containing either transformation enhancing or nonenhancing mutations at serine residues was generally similar to wild-type GAL4-Rel. However, more transforming mutants with mutations at either Ser460 or Ser471 differed from wild-type Rel in their ability to transactivate certain κ B-site reporter genes. In particular, the SOD2 promoter, encoding manganese superoxide dismutase, was activated less strongly by the more transforming Rel mutant Rel-S471N in transient assays, but Rel-S471N-transformed chicken spleen cells had increased levels of MnSOD protein as compared to wild-type Rel-transformed cells. Taken together, our results show that mutations of certain serine residues can enhance Rel's transforming ability in vitro and suggest that these mutations increase Rel-mediated transformation by altering Rel's ability to modulate the expression of select target genes. Furthermore, phosphorylation of Ser471 may be involved in Rel-mediated modulation of transformation-specific target gene expression. Lastly, these results suggest that similar mutations in the Rel transactivation domain contribute to the development of certain human B-cell lymphomas.
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Mutations of tumor necrosis Factor alpha-responsive serine residues within the C-terminal transactivation domain of human Transcription Factor Rel enhance its in vitro transforming ability.
Oncogene, 2005Co-Authors: Daniel T Starczynowski, Joseph G Reynolds, Thomas D GilmoreAbstract:The human c-Rel gene (Rel), encoding an NF-κB Transcription Factor, is amplified or mutated in several human B-cell lymphomas and can transform chicken lymphoid cells in vitro. We have previously shown that certain deletions of C-terminal transactivation sequences enhance Rel's transforming ability in chicken spleen cells. In this report, we have analysed the effect of single amino-acid changes at select serine residues in the C-terminal transactivation domain on Rel's transforming ability. Mutation of either of two TNFα-inducible serine residues (Ser460 and Ser471) to nonphosphorylatable residues (alanine, asparagine, phenylalanine) made Rel more efficient at transforming chicken spleen cells in vitro. In contrast, mutation of Ser471 to a phosphorylation mimetic aspartate residue impaired Rel's transforming ability, even though it increased Rel's inherent transactivation ability as a GAL4-fusion protein. Alanine mutations of several other serine residues within the transactivation domain did not substantially affect Rel's transforming ability. Transactivation by GAL4-Rel fusion proteins containing either transformation enhancing or nonenhancing mutations at serine residues was generally similar to wild-type GAL4-Rel. However, more transforming mutants with mutations at either Ser460 or Ser471 differed from wild-type Rel in their ability to transactivate certain κB-site reporter genes. In particular, the SOD2 promoter, encoding manganese superoxide dismutase, was activated less strongly by the more transforming Rel mutant Rel-S471N in transient assays, but Rel-S471N-transformed chicken spleen cells had increased levels of MnSOD protein as compared to wild-type Rel-transformed cells. Taken together, our results show that mutations of certain serine residues can enhance Rel's transforming ability in vitro and suggest that these mutations increase Rel-mediated transformation by altering Rel's ability to modulate the expression of select target genes. Furthermore, phosphorylation of Ser471 may be involved in Rel-mediated modulation of transformation-specific target gene expression. Lastly, these results suggest that similar mutations in the Rel transactivation domain contribute to the development of certain human B-cell lymphomas.
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Deletion of either C-terminal transactivation subdomain enhances the in vitro transforming activity of human Transcription Factor Rel in chicken spleen cells
Oncogene, 2003Co-Authors: Daniel T Starczynowski, Joseph G Reynolds, Thomas D GilmoreAbstract:The Rel gene is amplified in many human B-cell lymphomas and we have previously shown that expression of Rel from a retroviral vector can malignantly transform chicken spleen cells in vitro . To identify Rel protein functions necessary for malignant transformation, we have performed deletion analysis on Rel sequences encoding residues of two C-terminal subdomains that are involved in Transcriptional activation. We find that deletion of both C-terminal transactivation subdomains abolishes the ability of Rel to transform chicken spleen cells in vitro . In contrast, deletion of either transactivation subdomain alone, which reduces the transactivation ability of Rel, enhances the transforming activity of Rel. Transforming Rel mutants missing C-terminal sequences can also be selected at a low frequency in vitro . The Rel transactivation domain can be functionally replaced in transformation assays by a portion of the VP16 transactivation domain that activates at a level similar to Rel-transforming mutants. We also find that deletion of 29 C-terminal amino acids causes the subcellular localization of Rel to change from cytoplasmic to nuclear in chicken embryo fibroblasts. In contrast, wild-type Rel and all transforming Rel mutants are located primarily in the cytoplasm of transformed spleen cells. Nevertheless, treatment of transformed spleen cells with leptomycin B causes wild-type Rel and two Rel mutants to Relocalize to the nucleus, and nuclear extracts from these transformed cells contain Rel DNA-binding activity. Taken together, these results suggest the following: (1) that Rel must activate Transcription to transform cells in vitro ; (2) that a reduced level of transactivation enhances the oncogenicity of Rel; (3) that Rel shuttles from the cytoplasm to the nucleus in transformed chicken spleen cells; and (4) that mutations in Rel , in addition to amplifications, could activate its oncogenicity in human lymphomas.