Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27 Kip1

Department of Pathology and Graduate Program in Immunology and Microbial Pathogenesis, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2005; 101(51):17789-94. DOI: 10.1073/pnas.0406111101
Source: PubMed


Cell-cycle entry is critical for homeostatic control in physiologic response of higher organisms but is not well understood. The antibody response begins with induction of naive mature B cells, which are naturally arrested in G(0)/G(1) phase of the cell cycle, to enter the cell cycle in response to antigen and cytokine. BLyS (BAFF), a cytokine essential for mature B cell development and survival, is thought to act mainly by attenuation of apoptosis. Here, we show that BLyS alone induces cell-cycle entry and early G(1) cell-cycle progression, but not S-phase entry, in opposition to the cyclin-dependent kinase inhibitors p18(INK4c). Independent of its survival function, BLyS enhances the synthesis of cyclin D2, in part through activation of NF-kappaB, as well as CDK4 and retinoblastoma protein phosphorylation. By convergent activation of the same cell-cycle regulators in opposition to p18(INK4c), B cell receptor signaling induces cell-cycle entry and G(1) progression in synergy with BLyS, but also DNA replication. The failure of BLyS to induce S-phase cell-cycle entry lies in its inability to increase cyclin E and reduce p27(Kip1) expression. Antagonistic cell-cycle regulation by BLyS and p18(INK4c) is functionally linked to apoptotic control and conserved from B cell activation in vitro to antibody response in vivo, further indicating a physiologic role in homeostasis.

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    • "Given that MALT1 Ϫ / Ϫ mice exhibit a reduction in MZ and B1 B cells and that BCR signaling in MALT1 Ϫ / Ϫ B cells is synthesis ( Huang et al., 2004 ). BAFF-induced transitional B cell survival is required for the development of mature B cell subsets, including CD21 low CD23 high follicular (FO) B cells as well as CD21 high CD23 low marginal zone (MZ) B cells ( Batten et al., 2000 ). "
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    ABSTRACT: B cell activation factor of the TNF family (BAFF) activates noncanonical nuclear factor kappaB (NF-kappaB) heterodimers that promote B cell survival. We show that although MALT1 is largely dispensable for canonical NF-kappaB signaling downstream of the B cell receptor, the absence of MALT1 results in impaired BAFF-induced phosphorylation of NF-kappaB2 (p100), p100 degradation, and RelB nuclear translocation in B220(+) B cells. This corresponds with impaired survival of MALT1(-/-) marginal zone (MZ) but not follicular B cells in response to BAFF stimulation in vitro. MALT1(-/-) MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor-mediated signaling, and TRAF3 was found to interact with MALT1. Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numbers, elevated serum immunoglobulin titers, and spontaneous germinal center formation, were found to be dependent on B cell-intrinsic MALT1 expression. Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction.
    Journal of Experimental Medicine 11/2009; 206(12):2671-83. DOI:10.1084/jem.20091802 · 12.52 Impact Factor
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    • "Because B cell deficiency leads to increased levels of BAFF in both humans and mice (18, 51), we hypothesized that BAFF signals are involved in HP. Although B cells do not proliferate in response to BAFF in vitro, BAFF can induce entry into early G1 (52). Moreover, stimulation with BAFF leads to an increase in cell size and glucose metabolism (31), up-regulation of Ki-67, Cyclin D2, and Cdk4 expression, and phosphorylation of RB and Akt (53). "
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    ABSTRACT: We have characterized a distinct, late transitional B cell subset, CD21(int) transitional 2 (T2) B cells. In contrast to early transitional B cells, CD21(int) T2 B cells exhibit augmented responses to a range of potential microenvironmental stimuli. Adoptive transfer studies demonstrate that this subset is an immediate precursor of both follicular mature and marginal zone (MZ) B cells. In vivo, a large percentage of CD21(int) T2 B cells has entered the cell cycle, and the cycling subpopulation exhibits further augmentation in mitogenic responses and B cell-activating factor of the TNF family (BAFF) receptor expression. Consistent with these features, CD21(int) T2 cells exhibit preferential responses to BAFF-facilitated homeostatic signals in vivo. In addition, we demonstrate that M167 B cell receptor (BCR) idiotypic-specific B cells are first selected within the cycling CD21(int) T2 population, ultimately leading to preferential enrichment of these cells within the MZ B cell compartment. These data, in association with the coordinate role for BAFF and microenvironmental cues in determining the mature BCR repertoire, imply that this subset functions as a unique selection point in peripheral B cell development.
    Journal of Experimental Medicine 02/2008; 205(1):155-68. DOI:10.1084/jem.20071088 · 12.52 Impact Factor
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    • "However, the lack of BrdU incorporation in BAFF-treated cells shows that BAFF does not induce DNA-replication, thus precluding cell division. Previous findings show persistent expression of Cdk inhibitor proteins p18 and p27 in BAFF-treated cells (47). Therefore, it is likely that high expression of these and possibly other cell cycle inhibitors prevents the proliferation of BAFF-treated B cells in the absence of an antigenic signal. "
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    ABSTRACT: B cell life depends critically on the cytokine B cell-activating factor of the tumor necrosis factor family (BAFF). Lack of BAFF signaling leads to B cell death and immunodeficiency. Excessive BAFF signaling promotes lupus-like autoimmunity. Despite the great importance of BAFF to B cell biology, its signaling mechanism is not well characterized. We show that BAFF initiates signaling and transcriptional programs, which support B cell survival, metabolic fitness, and readiness for antigen-induced proliferation. We further identify a BAFF-specific protein kinase C beta-Akt signaling axis, which provides a connection between BAFF and generic growth factor-induced cellular responses.
    Journal of Experimental Medicine 11/2006; 203(11):2551-62. DOI:10.1084/jem.20060990 · 12.52 Impact Factor
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