Inducible resistance to Fas-mediated apoptosis in B cells

Rothstein, Thomas L.

doi:10.1038/sj.cr.7290053

Cited by 47 publications

(34 citation statements)

References 147 publications

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“…A critical step in the GC reaction occurs when CD40 on B cells binds its ligand, CD154, expressed on T and other cells, which may result in B cell proliferation, survival, or Ig class switch recombination (6). We postulate that this GC signal might, like BCR signaling, also repress TCL1 in Ramos B cells.…”

Section: Resultsmentioning

confidence: 99%

“…6E). Either CD40 or BCR signaling alone initiates apoptosis and negative selection in the absence of cosignaling (6,33,44). However, FAS-susceptible TCL1-repressed GC B cells can be rescued from death by TCL1-independent increases in the expression of BCL2L1 (Bcl-X L ) and CFLAR (Flip) (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

“…GC B cells undergo critical changes in gene expression that are required for proper development and protection from oncogenesis (4,5). The generation of an appropriate humoral response is insured by negative selection, primarily mediated by FAS-induced apoptosis (6)(7)(8). Escape from apoptosis results in autoimmunity and B cell transformation (8).…”

Section: Aberrant Expression Of the Tcl1 Oncoprotein Promotes Malignamentioning

confidence: 99%

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TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

Kuraishy

French

Sherman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Aberrant expression of the TCL1 oncoprotein promotes malignant transformation of germinal center (GC) B cells. Repression of TCL1in GC B cells facilitates FAS-mediated apoptosis and prevents lymphoma formation. However, the mechanism for this repression is unknown. Here we show that the CREB coactivator TORC2 directly regulates TCL1 expression independent of CREB Ser-133 phosphorylation and CBP/p300 recruitment. GC signaling through CD40 or the BCR, which activates pCREB-dependent genes, caused TORC2 phosphorylation, cytosolic emigration, and TCL1 repression. Signaling via cAMP-inducible pathways inhibited TCL1 repression and reduced apoptosis, consistent with a prosurvival role for TCL1 before GC selection and supporting an initiating role for aberrant TCL1 expression during GC lymphomagenesis. Our data indicate that a novel CREB/TORC2 regulatory mode controls the normal program of GC gene activation and repression that promotes B cell development and circumvents oncogenic progression. Our results also reconcile a paradox in which signals that activate pCREB/CBP/ p300 genes concurrently repress TCL1 to initiate its silencing.gene regulation ͉ lymphomagenesis ͉ signal transduction T he germinal center (GC) is home to T cell-dependent antigen-driven B cell maturation, memory B and plasma cell production, and the site of origin for most human B cell lymphomas (1-3). GC B cells undergo critical changes in gene expression that are required for proper development and protection from oncogenesis (4, 5). The generation of an appropriate humoral response is insured by negative selection, primarily mediated by FAS-induced apoptosis (6-8). Escape from apoptosis results in autoimmunity and B cell transformation (8).TCL1 functions as a coactivator of the cell survival kinase AKT (9, 10). In mature T cell tumors, TCL1 expression is aberrantly elevated by rearrangements into T cell receptor loci (11). Physiologic TCL1 expression is largely limited to B lineage cells and is robust from pre-B cells through peripheral naïve B cells, followed by a critical 40-60% repression in GC B cells and complete silencing in post-GC memory B and plasma cells (12,13). Most B cell lymphomas that arise by transformation of GC-experienced B cells exhibit elevated TCL1 expression by escape from GC mechanism(s) of TCL1 repression (12,14,15). Interestingly, transgenic mice with TCL1 expression levels stabilized in GC lymphocytes develop cancers that resemble a spectrum of human GC B cell lymphomas (16).Unrepressed TCL1 expression inhibits FAS-induced B cell apoptosis independent of activation by BCR survival signaling (17, 18). Impaired apoptosis from failed TCL1 repression in GC B cells connects TCL1 dysregulation in patient lymphomas (12, 14) to a mechanism for increased transformation (16,18). Factors so far suggested to regulate TCL1, including Nur77 (19,20), miRNA-29 and miRNA-181 (21), Sp1 (22), and EBV infection (23), fail to adequately explain TCL1 repression in GC B cells and its continued aberrant expression in lymphomas (11).Its role in ...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Aberrant Expression Of the Tcl1 Oncoprotein Promotes Malignamentioning

confidence: 99%

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TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

Kuraishy

French

Sherman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Programmed cell death or apoptosis plays important roles in development of animals from C. elegans, Drosophila, to human, and is critical for the physiological function of many organs, such as the immune system [50][51][52][53]. Anuran metamorphosis is a postembryonic process that is absolutely dependent upon the presence of TH.…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

Thyroid hormone regulation of apoptotic tissue remodeling during anuran metamorphosis

Shi

Hsia

et al. 2001

Cell Res

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Anuran metamorphosis involves systematic transformations of individual organs in a thyroid hormone (TH)-dependent manner. Morphological and cellular studies have shown that the removal of larval organs/ tissues such the tail and the tadpole intestinal epithelium is through programmed cell death or apoptosis. Recent molecular investigations suggest that TH regulates metamorphosis by regulating target gene expression through thyroid hormone receptors (TRs), which are DNA-binding transcription factors. Cloning and characterization of TH response genes show that diverse groups of early response genes are induced by TH. The products of these TH response genes are believed to directly or indirectly affect the expression and/or functions of cell death genes, which are conserved at both sequence and function levels in different animal species. A major challenge for future research lies at determining the signaling pathways leading to the activation of apoptotic processes and whether different death genes are involved in the regulation of apoptosis in different tissues/organs to effect tissue-specific transformations.

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“…Similarly, stimulation of naive B cells with CD40L (CD154) in vitro induces FAS expression on B cells and FASL sensitivity to cell death. 28 Subsequent engagement of the BCR by antigen (Ag) protects CD40-activated B cells from FAS-induced death by increasing the expression of BCL2L1 (Bcl-X L ) and CFLAR (Flip). [29][30][31] This BCR-mediated rescue signal probably acts to reinforce appropriate B-cell-T-cell interactions and eliminate illegitimate, non-Ag-driven B-cell expansion in the GC.…”

Section: B Cells With Heightened Tcl1 Expression Are More Resistant Tmentioning

confidence: 99%

Dysregulated TCL1 requires the germinal center and genome instability for mature B-cell transformation

Shen

Ferguson

Renard

et al. 2006

Blood

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IntroductionMost common B-cell lineage lymphomas in humans originate by transformation of germinal center (GC) B cells. These include classes of non-Hodgkin lymphoma (NHL) designated follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma (BL) as well as classical Hodgkin lymphoma. 1 FL and BL are characterized by recurring reciprocal chromosome (Chr) translocations that fuse Ig genes either with the BCL2 cell survival gene or with the MYC proto-oncogene, respectively. 2,3 Also, reciprocal Chr translocations involving the BCL6 transcriptional repressor gene and more than 20 partner loci, including the Ig genes, typify DLBCL. 4 These and additional tumor-promoting genes are subsequently expressed under the control of Ig regulatory sequences rather than their native regulatory elements, resulting in dysregulated expression. Interestingly, MYC, BCL6, and other genes, such as TCL1, are also expressed at high levels in many NHLs in the absence of activating translocations. In these cases, inappropriately high expression is a consequence of other genetic or possibly epigenetic alterations and is likely contributory to the transformation process. [5][6][7] The TCL1 proto-oncogene encodes a 14-kDa intracellular protein that associates in a multimeric complex with the serine/ threonine kinase AKT. [7][8][9][10][11] Interactions with TCL1 enhance AKT activation and, by an unknown mechanism, TCL1 stimulates the protein kinase C-mitogen-activated protein kinase-extracellular signal-related kinase (PKC-MAPK-ERK) signal transduction pathway, promoting cell survival and proliferation. 8,12,13 In human T cells, TCL1 is normally expressed only by immature cortical thymocytes and by activated peripheral T cells. 13,14 However, dysregulated expression from Chr rearrangements between TCL1 and T-cell receptor (TCR) loci results in persistent high-level expression in mature T-cell leukemia/lymphomas. 15 A direct, initiating role for heightened TCL1 expression in T-cell transformation is suggested by studies of transgenic mice with T-cell lineage-restricted TCL1 expression that develop mature T-cell leukemias following an extended premalignant phase of polyclonal expansion. 16 Despite its original identification in T-cell leukemias, TCL1 seems to have an even more prominent role in B cells and is For personal use only. on May 11, 2018. by guest www.bloodjournal.org From differentially expressed during normal B-cell maturation. Expression is robust from pre-B through follicular B-cell development, but is down-regulated during the GC reaction and is silenced in post-GC memory B and plasma cells. 17 High levels of TCL1 expression have been documented for human B-cell lymphomas originating from pre-GC and GC B cells and in AIDS-related lymphomas of post-GC cell origin. [17][18][19] The suggestion that inappropriately high expression in the GC could contribute to GC B-cell lymphomagenesis is strongly supported by studies of mice bearing a pE-B29-TCL1 transgene expressed in both T and B cells, which develop mat...

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Inducible resistance to Fas-mediated apoptosis in B cells

Cited by 47 publications

References 147 publications

TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation

Thyroid hormone regulation of apoptotic tissue remodeling during anuran metamorphosis

Dysregulated TCL1 requires the germinal center and genome instability for mature B-cell transformation

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