The suppression of SH3BGRL is important for v-Rel-mediated transformation

Majid, Shahana; Liss, Andrew S.; You, M. James; Bose, Henry R.

doi:10.1038/sj.onc.1209107

Cited by 33 publications

(34 citation statements)

References 78 publications

(81 reference statements)

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“…Whereas tumor suppressor alternative reading frame, UV-C, and certain chemotherapeutic drugs can induce RelA to repress transcription of antiapoptotic genes Bcl-xL, XIAP, and/or A20 to sensitize cells to apoptosis, v-Rel down-regulates SH3BGRL that severely impairs its transforming activity although its biological function remains to be determined (21,33,34,36,37). Here, we show that Rel proteins that can transform primary chicken lymphocytes, including a hRelA/v-Rel chimera, downregulate expression of BCR component IgE and BCR signaling adaptors BLNK and BCAP.…”

Section: Discussionmentioning

confidence: 99%

“…Although NF-nB is best known for its transcriptional activation function, recent work with RelA, RelB, and v-Rel showed that it can down-regulate specific genes and that these can significantly affect its role in apoptosis and oncogenesis (21,(32)(33)(34)(35). Whereas tumor suppressor alternative reading frame, UV-C, and certain chemotherapeutic drugs can induce RelA to repress transcription of antiapoptotic genes Bcl-xL, XIAP, and/or A20 to sensitize cells to apoptosis, v-Rel down-regulates SH3BGRL that severely impairs its transforming activity although its biological function remains to be determined (21,33,34,36,37).…”

Section: Discussionmentioning

confidence: 99%

“…v-Rel transcriptionally activates expression of c-Jun (AP-1), IRF-4, and IAP1 and promotes alternative splicing of telomerase reverse transcriptase, which play important roles in its ability to transform lymphocytes (17)(18)(19)(20). Additionally, recent work uncovered that v-Rel transcriptionally represses SH3BGRL and that this is also important for its transforming activity (21). Here, we show that both v-Rel and c-Rel lead to down-regulation of B-cell receptor (BCR)-signaling molecules B-cell adaptor for phosphoinositide 3-kinase (PI3K; BCAP) and B-cell linker (BLNK; BASH, SLP-65) and that this contributes significantly to v-Rel's transforming activity in lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

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Repression of B-Cell Linker (BLNK) and B-Cell Adaptor for Phosphoinositide 3-Kinase (BCAP) Is Important for Lymphocyte Transformation by Rel Proteins

et al. 2008

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Persistent Rel/nuclear factor-KB (NF-KB) activity is a hallmark of many human cancers, and the Rel proteins are implicated in leukemia/lymphomagenesis but the mechanism is not fully understood. Microarray analysis to identify transformationimpacting genes regulated by NF-KB's oncogenic v-Rel and c-Rel proteins uncovered that Rel protein expression leads to transcriptional repression of key B-cell receptor (BCR) components and signaling molecules like B-cell linker (BLNK), the B-cell adaptor for phosphoinositide 3-kinase (BCAP) and immunoglobulin L light chain (IgL), and is accompanied by a block in BCR-mediated activation of extracellular signalregulated kinase, Akt, and c-Jun-NH 2 -kinase in response to anti-IgM. The BLNK and BCAP proteins were also down-regulated in lymphoid cells expressing a transformation-competent chimeric RelA/v-Rel protein, suggesting a correlation with the capacity of Rel proteins to transform lymphocytes. DNA-binding studies identified functional NF-KB-binding sites, and chromatin immunoprecipitation (ChIP) data showed binding of Rel to the endogenous blnk and bcap promoters in vivo. Importantly, restoration of either BLNK or BCAP expression strongly inhibited transformation of primary chicken lymphocytes by the potent NF-KB oncoprotein v-Rel. These findings are interesting because blnk and other BCR components and signaling molecules are down-regulated in primary mediastinal large B-cell lymphomas and Hodgkin's lymphomas, which depend on c-Rel for survival, and are consistent with the tumor suppressor function of BLNK. Overall, our results indicate that downregulation of BLNK and BCAP is an important contributing factor to the malignant transformation of lymphocytes by Rel and suggest that gene repression may be as important as transcriptional activation for Rel's transforming activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Repression of B-Cell Linker (BLNK) and B-Cell Adaptor for Phosphoinositide 3-Kinase (BCAP) Is Important for Lymphocyte Transformation by Rel Proteins

et al. 2008

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“…902 While the latter has been shown to contribute to Rel-903 mediated transformation when inactivated [148], so 904 such role has yet been identified in the former. Interestingly, 11p has been reported with reduced 992 copy number in melanoma [25].…”

Section: Q141 901mentioning

confidence: 99%

Copy number variation in archival melanoma biopsies versus benign melanocytic lesions

Mahas

Potluri

Kent

et al. 2016

CBM

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Abstract. BACKGROUND: Skin melanocytes can give rise to benign and malignant neoplasms. Discrimination of an early melanoma from an unusual/atypical benign nevus can represent a significant challenge. However, previous studies have shown that in contrast to benign nevi, melanoma demonstrates pervasive chromosomal aberrations. OBJECTIVE: This substantial difference between melanoma and benign nevi can be exploited to discriminate between melanoma and benign nevi. METHODS: Array-comparative genomic hybridization (aCGH) is an approach that can be used on DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues to assess the entire genome for the presence of changes in DNA copy number. In this study, high resolution, genome-wide single-nucleotide polymorphism (SNP) arrays were utilized to perform comprehensive and detailed analyses of recurrent copy number aberrations in 41 melanoma samples in comparison with 21 benign nevi. RESULTS: We found statistically significant copy number gains and losses within melanoma samples. Some of the identified aberrations are previously implicated in melanoma. Moreover, novel regions of copy number alterations were identified, revealing new candidate genes potentially involved in melanoma pathogenesis. CONCLUSIONS: Taken together, these findings can help improve melanoma diagnosis and introduce novel melanoma therapeutic targets.Keywords: Array comparative genomic hybridization, melanoma, FFPE highly lethal forms of cancer. Although it accounts 10 for the minority of skin cancers, a large majority 11 (75%) of skin cancer related-deaths are accounted for 12 by melanoma [1,2]. The incidence and mortality of 13 melanoma has increased dramatically in the last few 14 decades [3]. The American Cancer Society estimates 15 that about 73,870 people in United States will be diag-16 nosed with melanoma in 2015 and about 9,940 people 17 are expected to die from the disease. Importantly, the 18 5-year survival rate of melanoma depends on the stage 19 of the disease when it is diagnosed. It can be as high 20 as 98% when the melanoma is detected early before 21 it spreads to the lymph nodes or other organs. When 22 melanoma reaches the lymph nodes, the 5-year sur-23 vival rate drops to 62%, and to 15% when melanoma 24 spread to other organs [2]. Sequences for the primer pairs and cycling parame-286 ters were as follows: 5'-AATCGGGCTG-3' and 5'-287 GAAACGGGTG-3', 94• C for 2.5 minutes, then 45 cy-288 cles of 1 minute 94• C, 1 minute 55 • C and 2 minutes 289 72• C, then 7 minutes 72 • C and holding at 4 • C; or 5 -290 TGTGCCCAGTGAAGACTCAG-3' and 5 -GAGTGA 291 GCGGAGAGGGAACT-3', 45 cycles of 94• C for 1 292 minute, 35• C for 1 minute, and 72• C for 2 minute. 293 PCR products were resolved on 3% TBE agarose plus 294 SYBR Safe dye (Life Technologies). Gels were visu-295 alized with a GE ImageQuant LAS-3000 camera (GE 296 Healthcare Life Sciences, Piscataway, NJ, USA). Microarrays 298DNA copy number analysis was performed by hy-299 bridizing the extracted and qualified gDNA to Affy-300 metrix...

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“…While RelA failed to transform chicken lymphoid cells on its own, replacement of RelA's TAD with that of either v-Rel or c-Rel conferred a strong transforming phenotype both in vitro and in vivo (13). Recent work showed that in addition to activating expression of antiapoptotic and proproliferative genes, the Rel TADs can also lead to gene-specific transcriptional repression of genes such as those for SH3BGRL and the B-cell receptor signaling molecules BCAP and BLNK, and this activity is as important for lymphocyte transformation by v-Rel as is its transactivation function (19,35). Additionally v-Rel can promote expression and alternative splicing of telomerase reverse transcriptase (TERT), which is also involved in lymphocyte transformation (24).…”

mentioning

confidence: 99%

CAPERα Is a Novel Rel-TAD-Interacting Factor That Inhibits Lymphocyte Transformation by the Potent Rel/NF-κB Oncoprotein v-Rel

Dutta

Fan

Gélinas

2008

J Virol

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The Rel/NF-B family of transcription factors is key for immune and inflammatory responses and also controls cell proliferation and apoptosis. The v-Rel oncoprotein of reticuloendotheliosis virus strain T (Rev-T) is the most potent oncogenic member of this family. Both v-Rel and its cellular homologue c-Rel transform primary splenic lymphocytes in vitro and cause fatal leukemia/lymphomas in chickens and transgenic mice (5,9,17,22,23,33,38,39). This agrees with the implication of Rel/NF-B in the pathogenesis and chemoresistance of many hematopoietic and solid tumors, including primary mediastinal B-cell lymphomas (PMBCL) and classical Hodgkin's lymphoma, in which constitutively high levels of nuclear c-Rel protein are necessary for tumor cell survival and proliferation (3,4,14,18,20,27,49). Additionally, some PMBCL and follicular lymphomas harbor c-rel gene mutations that decrease c-Rel's transactivation potency and enhance its transforming activity in primary chicken lymphocytes (45). This is consistent with the increased transforming phenotype conferred by certain mutations in v-Rel and c-Rel and indicates that modulation of Rel's transcriptional activity can significantly affect its oncogenicity (12,43,44).The Rel proteins bind to B DNA sites as homo-or heterodimers with other NF-B family members via their N-terminal Rel homology domain (RHD), which also mediates nuclear localization and association with inhibitory IB subunits.

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The suppression of SH3BGRL is important for v-Rel-mediated transformation

Cited by 33 publications

References 78 publications

Repression of B-Cell Linker (BLNK) and B-Cell Adaptor for Phosphoinositide 3-Kinase (BCAP) Is Important for Lymphocyte Transformation by Rel Proteins

Repression of B-Cell Linker (BLNK) and B-Cell Adaptor for Phosphoinositide 3-Kinase (BCAP) Is Important for Lymphocyte Transformation by Rel Proteins

Copy number variation in archival melanoma biopsies versus benign melanocytic lesions

CAPERα Is a Novel Rel-TAD-Interacting Factor That Inhibits Lymphocyte Transformation by the Potent Rel/NF-κB Oncoprotein v-Rel

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