Cyclin D3 Compensates for Loss of Cyclin D2 in Mouse B-lymphocytes Activated via the Antigen Receptor and CD40

Lam, Eric W.‐F.; Glassford, Janet; Banerji, Lolita; Thomas, N. Shaun B.; Siciński, Piotr; Klaus, G. G. B.

doi:10.1074/jbc.275.5.3479

Cited by 110 publications

(101 citation statements)

References 39 publications

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“…21 Mature B lymphocytes express cyclins D2 and D3, but not cyclin D1 after B-cell receptor crosslinking. Importantly, when cyclin D2 22 or cyclin D3 23 is disrupted in B cells in vitro, the remaining functional D-type cyclins compensate for the loss, indicating that there is a high level of functional redundancy among D-type cyclins. To prove this hypothesis, double knockdown of cyclins D1 and D2 was Cyclin D1 knockdown in MCL M Klier et al performed.…”

Section: Discussionmentioning

confidence: 99%

Specific lentiviral shRNA-mediated knockdown of cyclin D1 in mantle cell lymphoma has minimal effects on cell survival and reveals a regulatory circuit with cyclin D2

et al. 2008

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Cyclin D1 overexpression is the hallmark of mantle cell lymphoma (MCL). However, the importance of cyclin D1 in the maintenance and progression of the disease remains to be defined. The aim of this study was to elucidate the role of cyclin D1 overexpression using an efficient cyclin D1-shRNA and a lentiviral system in well-characterized MCL cell lines. Surprisingly, the knockdown of cyclin D1 led to a moderate retardation in growth, without induction of apoptosis. The cyclin D1-shRNA-transduced MCL cells showed a 15% shift from S phase to G 1 phase of the cell cycle, a weak induction of p27 Kip1 , decreased Rb (Ser807/811) phosphorylation, and a consistent upregulation of cyclin D2 mRNA and protein expression. However, double knockdown of cyclins D1 and D2 did not intensify the effects observed with cyclin D1 knockdown alone. These data suggest that the moderate effects of cyclin D1 downregulation on survival and proliferation are likely the result of compensatory cyclin-independent mechanisms governing proliferation or alternatively, secondary genetic events that make cyclin D1 dispensable. These findings have important implications for MCL therapy, as strategies targeting only cyclin D1 function might be hampered by compensatory regulatory mechanisms, resulting in a low probability of treatment response.

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Section: Discussionmentioning

confidence: 99%

Specific lentiviral shRNA-mediated knockdown of cyclin D1 in mantle cell lymphoma has minimal effects on cell survival and reveals a regulatory circuit with cyclin D2

et al. 2008

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“…Cyclin D1 has been shown to regulate the timing of G 1 -S as fibroblasts lacking cyclin D1 have delayed progression into S phase, but still progress through the cell cycle (72). It is possible that the lack of cyclin D1 is compensated by other D type cyclins (72,73) or cyclins A or E, which also act upon the Rb-E2F regulation of the cell cycle. The mechanism by which activated Raf and MEK drive progression into S phase may be related to expression of cyclin E, which appears higher in cells transfected with activated Ras pathway mutants.…”

Section: Discussionmentioning

confidence: 99%

The Role of Collagen Structure in Mitogen Stimulation of ERK, Cyclin D1 Expression, and G1-S Progression in Rat Hepatocytes

Fassett

Tobolt

Nelsen

et al. 2003

Journal of Biological Chemistry

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Adhesion to type 1 collagen can elicit different cellular responses dependent upon whether the collagen is in a fibrillar form (gel) or monomeric form (film). Hepatocytes adherent to collagen film spread extensively, express cyclin D1, and increase DNA synthesis in response to epidermal growth factor, whereas hepatocytes adherent to collagen gel have increased differentiated function, but lower DNA synthesis. The signaling mechanisms by which different forms of type I collagen modulate cell cycle progression are unknown. When ERK MAP kinase activation was analyzed in hepatocytes attached to collagen film, two peaks of ERK activity were demonstrated. Only the second peak, which correlated with an increase of cyclin D1, was required for G 1 -S progression. Notably, this second peak of ERK activity was absent in cells adherent to collagen gel, but not required in the presence of exogenous cyclin D1. Expression of activated mutants of the Ras/Raf/MEK signaling pathway in cells adherent to collagen gel restored ERK phosphorylation and DNA synthesis, but differentially affected cell shape. Although Ras, Raf, and MEK all increased expression of cyclin D1 on collagen film, only Ras and Raf significantly up-regulated cyclin D1 levels on collagen gel. These results demonstrate that adhesion to polymerized collagen induces growth arrest by inhibiting the Ras/ERK-signaling pathway to cyclin D1 required in late G 1 .

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“…Mice deleted of components of the B-cell signalosome display 'Xid' phenotypes, including loss of B1 cells, reduced serum IgM and IgG3 levels, impaired Tindependent antibody response and absence of B cell proliferative response to anti-IgM (Fruman et al, 2000;DeFranco, 2001), which are also shared by cyclin D2-deficient mice (Solvason et al, 1998;Lam et al, 2000). The present finding that cyclin D2 functions downstream of the B-cell signalosome on the BCR signalling axis provides biochemical evidence to explain the genetic link between cyclin D2 and signalling intermediates of the B cell signalosome.…”

Section: Discussionmentioning

confidence: 99%

BCR targets cyclin D2 via Btk and the p85α subunit of PI3-K to induce cell cycle progression in primary mouse B cells

et al. 2003

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The p85a subunit of PI3-K and Btk are two crucial components of the B-cell receptor (BCR) signalling pathway. In the present study, we showed that primary splenic B cells from p85a null and xid (Btk-deficient) mice fail to induce cyclin D2 expression and enter early G1, but not S phase of the cell cycle in response to BCR engagement. Furthermore, these Btk or p85a null B cells displayed increased cell death compared with wild type following BCR engagement. These findings are further confirmed by studies showing that specific pharmacological inhibitors of Btk (LFM-A13), PI3-K (LY294002 and Wortmannin) and PLCc (U73122) also block cyclin D2 expression and S phase entry following BCR stimulation, as well as triggering apoptosis. Collectively, these data provide evidence for the concept that the B-cell signalosome (p85a, Btk, BLNK and PLCc) is involved in regulating cyclin D2 expression in response to BCR engagement. PKC and intracellular calcium are two major downstream effectors of the B-cell signalosome and can be activated by PMA and ionomycin, respectively. In small resting (G0) B cells, costimulation with PMA and ionomycin, but not PMA or ionomycin alone, induces cyclin D2 expression and cell-cycle progression. Consistent with this, we also showed that the BCR-mediated cyclin D2 induction could be abolished by pretreatment of resting B cells with specific inhibitors of capacitative Ca 2+ entry (SK&F 96365) or PKC (Go¨6850). Our present results lead us to propose a model in which the B-cell signalosome targets cyclin D2 via the Ca 2+ and PKCdependent signalling cascades to mediate cell-cycle progression in response to BCR engagement.

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Cyclin D3 Compensates for Loss of Cyclin D2 in Mouse B-lymphocytes Activated via the Antigen Receptor and CD40

Cited by 110 publications

References 39 publications

Specific lentiviral shRNA-mediated knockdown of cyclin D1 in mantle cell lymphoma has minimal effects on cell survival and reveals a regulatory circuit with cyclin D2

Specific lentiviral shRNA-mediated knockdown of cyclin D1 in mantle cell lymphoma has minimal effects on cell survival and reveals a regulatory circuit with cyclin D2

The Role of Collagen Structure in Mitogen Stimulation of ERK, Cyclin D1 Expression, and G1-S Progression in Rat Hepatocytes

BCR targets cyclin D2 via Btk and the p85α subunit of PI3-K to induce cell cycle progression in primary mouse B cells

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