Antigen receptor-induced cell cycle arrest in WEHI-231 B lymphoma cells depends on the duration of signaling before the G1 phase restriction point.

Page, Dawne M.; DeFranco, A L

doi:10.1128/mcb.10.6.3003

Cited by 46 publications

(23 citation statements)

References 36 publications

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“…2D). It was previously reported that BCR crosslinking induced G 0 /G 1 arrest of WEHI-231 cells before the induction of apoptosis (10,11). Anti-IgM stimulation induced a similar level of G 0 /G 1 arrest in transfectants with WT and S62A mutant Bcl-xL (Supplemental Fig.…”

Section: Phosphorylation Of Ser 62 Of Bcl-xl Is Important For Its Ubimentioning

confidence: 63%

“…We studied the apoptosis-induction system of WEHI-231 cells that undergo growth arrest and apoptosis following crosslinking of IgM on the cell surface, which mimics the deletion of self-reactive B cells in the bone marrow (8)(9)(10)(11). Anti-IgM stimulation induces cell death in 12-24 h. WEHI-231 cells were cultured in the presence of 10 mg/ml of anti-IgM, and expression of the antiapoptotic factor Bcl-xL was assessed by Western blot.…”

Section: Bcr Crosslinking In Wehi-231 Cells Induces Bcl-xl Degradatiomentioning

confidence: 99%

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Protein Phosphatase 6 Controls BCR-Induced Apoptosis of WEHI-231 Cells by Regulating Ubiquitination of Bcl-xL

Kajihara

Sakamoto

Tanabe

et al. 2014

The Journal of Immunology

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Crosslinking BCR in the immature B cell line WEHI-231 causes apoptosis. We found that Bcl-xL was degraded by polyubiquitination upon BCR crosslinking and in this study explored the mechanism that controls the degradation of Bcl-xL. Ser62 of Bcl-xL was phosphorylated by JNK to trigger polyubiquitination, and this was opposed by serine/threonine protein phosphatase 6 (PP6) that physically associated with Bcl-xL. We show BCR crosslinking decreased PP6 activity to allow Ser62 phosphorylation of Bcl-xL. CD40 crosslinking rescues BCR-induced apoptosis, and we found PP6 associated with CD40 and PP6 activation in response to CD40. Our data suggest that PP6 activity is regulated to control apoptosis by modulating Ser62 phosphorylation of Bcl-xL, which results in its polyubiquitination and degradation.

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Section: Phosphorylation Of Ser 62 Of Bcl-xl Is Important For Its Ubimentioning

confidence: 63%

Section: Bcr Crosslinking In Wehi-231 Cells Induces Bcl-xl Degradatiomentioning

confidence: 99%

Protein Phosphatase 6 Controls BCR-Induced Apoptosis of WEHI-231 Cells by Regulating Ubiquitination of Bcl-xL

Kajihara

Sakamoto

Tanabe

et al. 2014

The Journal of Immunology

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“…Cross-linking of membrane IgM on WEHI-231 cells results in growth arrest and the induction of apoptosis (31)(32)(33). Because of this functional response, WEHI-231 cells have been used extensively as a model for immature B cell negative selection.…”

Section: Hsh2 Protects Wehi-231 Cells From Undergoing Bcr-induced Apomentioning

confidence: 99%

The Adaptor Protein HSH2 Attenuates Apoptosis in Response to Ligation of the B Cell Antigen Receptor Complex on the B Lymphoma Cell Line, WEHI-231

Herrin

Groeger

Justement

2005

Journal of Biological Chemistry

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Signals transduced by the B cell antigen receptor (BCR) play a central role in regulating the functional response of the cell to antigen. Depending on the nature of the antigenic signal and the developmental or differentiation state of the B cell, antigen receptor signaling can promote either apoptosis or survival and activation. Understanding the molecular mechanisms underlying BCR-mediated apoptosis constitutes an important area of research because aberrations in programmed cell death can result in the development of autoimmunity or cancer. Expression of the adaptor protein hematopoietic Src homology 2 (HSH2) was found to significantly decrease BCR-mediated apoptosis in the murine WEHI-231 cell line. Analysis of signal transduction pathways activated in response to BCR ligation revealed that HSH2 does not significantly alter total protein tyrosine phosphorylation or Ca 2؉ mobilization. HSH2 does not potentiate the activation-dependent phosphorylation of AKT either. With respect to MAPK activation, HSH2 was not observed to alter the activation of ERK or p38 in response to BCR ligation, but it does significantly potentiate JNK activation. Analysis of processes directly associated with apoptosis revealed that HSH2 inhibits mitochondrial depolarization to a significant degree, whereas it has only a slight effect on caspase activation and poly ADP-ribose polymerase cleavage. BCR-induced apoptosis of WEHI-231 cells is associated with the loss of endogenous HSH2 expression within 12 h, whereas inhibition of apoptosis in response to CD40-mediated signaling leads to stabilization of HSH2 expression. Thus, endogenous HSH2 expression correlates directly with survival of WEHI-231 cells, which supports the hypothesis that HSH2 modulates the apoptotic response through its ability to directly or indirectly promote mitochondrial stability.

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“…On the other hand, the ectopic expression of cyclin A and E, the activating partners of Cdk2, can overcome pRbmediated growth arrest in G1 by inducing pRb hyperphosphorylation (Hinds et al, 1992). Because anti-IgM prevents phosphorylation of pRb in WEHI-231 cells only when added in early G1 (Joseph et al, 1995), and leads to growth arrest near the G1/S border without affecting the duration of G1 (Page and DeFranco, 1990), we set out to determine whether negative signaling affects the accumulation and activity of cyclin A or cyclin E-associated kinase complexes. Although cyclin A proteins were easily detected in lysates of WEHI-231 cells by immunoblotting and immunoprecipitation, the level of cyclin E expression was very low even in exponentially growing cells, as reported recently for murine splenic B-cells (Tanguay and Chiles, 1994).…”

Section: Introductionmentioning

confidence: 99%

Role of cyclin A and p27 in anti-IgM induced G1 growth arrest of murine B-cell lymphomas.

Ezhevsky

Toyoshima

Hunter

et al. 1996

MBoC

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Cross-linking surface immunoglobulin (Ig)M on the WEHI-231 B-cell lymphoma results in decreased cell size, G1/S growth arrest, and finally DNA cleavage into oligonucleosomal fragments that are the classical features of apoptotic cells. Treatment of WEHI-231 cells with anti-IgM in early G1 phase prevents phosphorylation of the retinoblastoma gene product (pRb) and inhibits entry into S phase. Using unsynchronized cells, we previously demonstrated that cyclin A-associated and Cdk2-dependent GST-pRb kinase activity were inhibited in WEHI-231 cells treated with anti-IgM. We now show that progression of elutriated early G1 phase VVEHI-231 cells from early into late G1 phase is accompanied by an increase in the abundance of cyclin A protein and cyclin A-associated kinase activity. Treatment of early G1 cells with anti-IgM prevented this increase in cyclin A-associated kinase activity at late G1, despite minimal changes in the overall level of cyclin A and Cdk2 proteins. Late G1 cells, which already possess high cyclin A-associated kinase activity, were insensitive to anti-IgM treatment and were able to complete the cell cycle. We also found that anti-IgM-treated cells contained increased amounts of the Cdk inhibitor protein p27K1Pl. Essentially all of the cycin A in treated cells was associated with p27, a result which we propose explains the lack of cyclin A/Cdk2 kinase activity. Accumulation of p27 in cyclin A kinase complexes, however, did not decrease the amount of Cdk2 bound to cyclin A. Thus, cross-linking IgM on growth-inhibitable B-cell lymphomas affects cyclin A kinase activity by increasing the levels of p27 in this complex, thus preventing productive pRb phosphorylation and leading to cell cycle arrest and subsequent apoptosis. These results are discussed in terms of the cell cycle restriction points that regulate lymphocyte function, as well as the lineage-specific differences in cell cycle control.

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Antigen receptor-induced cell cycle arrest in WEHI-231 B lymphoma cells depends on the duration of signaling before the G1 phase restriction point.

Abstract: The murine B lymphoma cell line WEHI-231 has been extensively used to study antigen receptor regulation of B-cell growth (11,14,15,20,23,31

Cited by 46 publications

References 36 publications

Protein Phosphatase 6 Controls BCR-Induced Apoptosis of WEHI-231 Cells by Regulating Ubiquitination of Bcl-xL

Protein Phosphatase 6 Controls BCR-Induced Apoptosis of WEHI-231 Cells by Regulating Ubiquitination of Bcl-xL

The Adaptor Protein HSH2 Attenuates Apoptosis in Response to Ligation of the B Cell Antigen Receptor Complex on the B Lymphoma Cell Line, WEHI-231

Role of cyclin A and p27 in anti-IgM induced G1 growth arrest of murine B-cell lymphomas.

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