Subnuclear cyclin D3 compartments and the coordinated regulation of proliferation and immunoglobulin variable gene repression (original) (raw)
Related papers
A unique function for cyclin D3 in early B cell development
Nature Immunology, 2006
During hematopoiesis, stem cell proliferation is dependent on expression of the D-type cyclins. However, little is known about how each cyclin D contributes to the development of specific hematopoietic lineages. Here, analysis of Ccnd1 -/-, Ccnd2 -/-, Ccnd3 -/and Ccnd2 -/-Ccnd3 -/mice showed that cyclin D3 was uniquely required for the development of pre-B cells. Transcription of Ccnd3 was dependent on expression of the common c-chain. In contrast, expression of the pre-B cell receptor and activation of 'downstream' signaling pathways prevented proteasome-mediated degradation of cyclin D3. Cyclin D3 has a key function in B cell development by integrating cytokine and pre-B cell receptor-dependent signals to expand the pool of pre-B cells that have successfully rearranged immunoglobulin heavy chain.
Background: The family of D cyclins has a fundamental role in cell cycle progression, but its members (D1, D2, D3) are believed to have redundant functions. However, there is some evidence that contradicts the notion of mutual redundancy and therefore this concept is still a matter of debate. Results: Our data show that the cyclin D1 is indispensable for normal hematopoiesis. Indeed, in the absence of D1, either in genetic deficient mice, or after acute ablation by RNA interference, cyclins D2 and D3 are also not expressed preventing hematopoietic cell division and differentiation at its earliest stage. This role does not depend on the cyclin box, but on the carboxyl regulatory domain of D1 coded by exons 4-5, since hematopoietic differentiation is also blocked by the conditional ablation of this region. Conclusion: These results demonstrate that not all functions of individual D cyclins are redundant and highlight a master role of cyclin D1 in hematopoiesis.
Cyclin D2controls B cell progenitor numbers
Journal of Leukocyte Biology, 2003
Cyclin D2 affects B cell proliferation and differentiation in vivo. It is rate-limiting for B cell receptor (BCR)-dependent proliferation of B cells, and cyclin D2 ؊/؊ mice lack CD5؉(B1) B lymphocytes. We show here that the bone marrow (BM) of cyclin D2 ؊/؊ mice contains half the numbers of Sca1؉B220؉ B cell progenitors but normal levels of Sca1؉ progenitor cells of other lineages. In addition, clonal analysis of BM from the cyclin D2 ؊/؊ and cyclin D2 ؉/؉ mice confirmed that there were fewer B cell progenitors (B220؉) in the cyclin D2 ؊/؊ mice. In addition, the colonies from cyclin D2 ؊/؊ mice were less mature (CD19 lo) than those from cyclin D2 ؉/؉ mice (CD19 Hi). The number of mature B2 B cells in vivo is the same in cyclin D2 ؊/؊ and cyclin D2 ؉/؉ animals. Lack of cyclin D2 protein may be compensated by cyclin D3, as cyclin-dependent kinase (cdk)6 coimmunoprecipitates with cyclin D3 but not cyclin D1 from BM mononuclear cells of cyclin D2 ؊/؊ mice. It is active, as endogenous retinoblastoma protein is phosphorylated at the cdk6/4-cyclin D-specific sites, S 807/811. We conclude that cyclin D2 is ratelimiting for the production of B lymphoid progenitor cells whose proliferation does not depend on BCR signaling.
I B Kinase Regulates Subcellular Distribution and Turnover of Cyclin D1 by Phosphorylation
Journal of Biological Chemistry, 2005
IB kinases (IKKs), IKK␣ and IKK, with a regulatory subunit IKK␥/NEMO constitute a high molecular weight IKK complex that regulates NF-B activity. Although IKK␣ and IKK share structural and biochemical similarities, IKK␣ has been shown to have distinct biological roles. Here we show that IKK␣ plays a critical role in regulating cyclin D1 during the cell cycle. Analysis of IKK␣ ؊/؊ mouse embryo fibroblast cells showed that cyclin D1 is overexpressed and localized in the nucleus compared with parental mouse embryo fibroblasts. IKK␣ associates with and phosphorylates cyclin D1. Analysis on cyclin D1 mutants demonstrated that IKK␣ phosphorylates cyclin D1 at Thr 286 . Reconstitution of IKK␣ in knockout cells leads to nuclear export and increased degradation of cyclin D1. Further, RNAi-mediated knockdown of IKK␣ results in similar changes as observed in IKK␣ ؊/؊ cells. These results suggest a novel role of IKK␣ in regulating subcellular localization and proteolysis of cyclin D1 by phosphorylation of cyclin D1 at Thr 286 , the same residue earlier found to be a target for glycogen synthase kinase-3induced phosphorylation.
Requirement for cyclin D3 in lymphocyte development and T cell leukemias
Cancer Cell, 2003
The D-type cyclins (cyclins D1, D2, and D3) are components of the core cell cycle machinery in mammalian cells. Cyclin D3 gene is rearranged and the protein is overexpressed in several human lymphoid malignancies. In order to determine the function of cyclin D3 in development and oncogenesis, we generated and analyzed cyclin D3-deficient mice. We found that cyclin D3 Ϫ/Ϫ animals fail to undergo normal expansion of immature T lymphocytes and show greatly reduced susceptibility to T cell malignancies triggered by specific oncogenic pathways. The requirement for cyclin D3 also operates in human malignancies, as knock-down of cyclin D3 inhibited proliferation of acute lymphoblastic leukemias deriving from immature T lymphocytes. These studies point to cyclin D3 as a potential target for therapeutic intervention in specific human malignancies.
Experimental Cell Research, 2007
Cyclin D1 is an important regulator of the early phase of the cell cycle and the transcriptional machinery. It is often deregulated in human tumors of various origins and is considered to be an oncogene. The CCND1 gene encoding cyclin D1 generates two mRNAs by alternative splicing, leading to the production of two alternative proteins: a long form a (36 kDa) and a short form b (30-31 kDa) from which the C-terminal moiety required for protein stability and sub-cellular localization has been deleted. Both forms of RNA and protein have been detected in B-cell hemopathies, but their respective roles are unclear. We investigated the function of cyclin D1b in cell cycle regulation, by generating B-cell lines displaying conditional expression of isoform b. Comparisons of these cell lines (BD1b series) with previously obtained cell lines expressing cyclin D1a demonstrated that cyclin D1b had no cell cycle regulatory properties.
FEBS Journal, 2006
Progression through the eukaryotic cell division cycle is directed by the activity of protein kinase complexes. These complexes are composed of a cyclin as regulating subunit and a cyclin-dependent kinase (cdk) as a catalytically active component. Cyclins activate cdks and thereby regulate transition through the cell cycle. Thus, fundamental control of the cell cycle is based on regulated cyclin synthesis and regulated destruction during progression through cell division . Besides their importance for appropriate timing of cdk activity, cyclins also determine cdk substrate specificity [2]. The first identified cyclin ⁄ cdk complex, composed of cyclin B and cdk1 (cdc2), was the maturation-promoting factor (MPF). The complex is conserved in all eukaryotes. MPF controls the G 2 ⁄ M checkpoint since it is indispensable for the transition from G 2 phase to mitosis .
Mammalian Cells Cycle without the D-Type Cyclin-Dependent Kinases Cdk4 and Cdk6
Cell, 2004
highlighted by the fact that pRb can bind more than 120 and Mariano Barbacid 1, * cellular proteins (Morris and Dyson, 2001). 1 Molecular Oncology Program Phosphorylation of pRb by D-type cyclin/Cdk4 or Centro Nacional de Investigaciones Oncoló gicas (CNIO) Cdk6 complexes results in its partial inactivation, which E-28029 Madrid in turn allows expression of a limited number of tran-Spain scriptional targets needed to drive cells through the G1 2 EA2406 University of Bordeaux 2 phase of the cell cycle. For instance, some of these F-33076 Bordeaux targets are additional cyclins, such as the E-type cyclins France (E1 and E2), whose primary role is to activate Cdk2. Active E-type cyclin/Cdk2 complexes further phosphorylate pRb (Lundberg and Weinberg, 1998; Harbour et Summary al., 1999) leading to a wave of transcriptional activity essential to proceed through the G1/S transition. How-Cdk4 and Cdk6 are thought to be essential for initiation ever, recent genetic evidence indicating that Cdk2 and of the cell cycle in response to mitogenic stimuli. Previ-E-type cyclins are not required for mitotic cell division ous studies have shown that Cdk4 is dispensable for has challenged this model (Berthet et al., 2003; Ortega et proliferation in most cell types, an observation attribal., 2003; Geng et al., 2003; Parisi et al., 2003)
Cell Proliferation, 2008
Objectives : This article is to study the role of G 1 /S regulators in differentiation of pluripotent embryonic cells. Materials and methods : We established a P19 embryonal carcinoma cell-based experimental system, which profits from two similar differentiation protocols producing endodermal or neuroectodermal lineages. The levels, mutual interactions, activities, and localization of G 1 /S regulators were analysed with respect to growth and differentiation parameters of the cells. Results and Conclusions : We demonstrate that proliferation parameters of differentiating cells correlate with the activity and structure of cyclin A/E-CDK2 but not of cyclin D-CDK4/6-p27 complexes. In an exponentially growing P19 cell population, the cyclin D1-CDK4 complex is detected, which is replaced by cyclin D2/3-CDK4/6-p27 complex following density arrest. During endodermal differentiation kinase-inactive cyclin D2/D3-CDK4-p27 complexes are formed. Neural differentiation specifically induces cyclin D1 at the expense of cyclin D3 and results in predominant formation of cyclin D1/D2-CDK4-p27 complexes. Differentiation is accompanied by cytoplasmic accumulation of cyclin Ds and CDK4/6, which in neural cells are associated with neural outgrowths. Most phenomena found here can be reproduced in mouse embryonic stem cells. In summary, our data demonstrate (i) that individual cyclin D isoforms are utilized in cells lineage specifically, (ii) that fundamental difference in the function of CDK4 and CDK6 exists, and (iii) that cyclin D-CDK4/6 complexes function in the cytoplasm of differentiated cells. Our study unravels another level of complexity in G 1 /S transition-regulating machinery in early embryonic cells.
Phenotype-related differences in the expression of D-type cyclins in human B cell-derived lines
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 1996
Exposure of normal resting B lymphocytes to EBV in vitro leads to activation, subsequent immortalization, and the establishment of lymphoblastoid cell lines (LCLs). The endemic form of Burkitt's lymphoma (BL) is associated with EBV. EBV-positive BL lines maintain the original tumor phenotype (group I BL) initially and express only one EBV-encoded protein, EBV nuclear antigen (EBNA)-1. Most of them drift toward a LCL-like phenotype during in vitro culturing and express all nine EBV-encoded growth transformation-associated proteins (group III BL). Cyclin D2 and D3 have been found previously to differ in their mRNA expression in BL and LCL. Cyclin D2 expression has been attributed to EBV gene expression and to EBNA-2 and EBNA-5 in particular. We have studied cyclin D2/D3 expression in larger series of LCLs, BL lines, and freshly EBV-infected peripheral blood B lymphocytes, both at the mRNA and protein levels. The predominant cyclin D2 expression in the LCLs and group III BLs correl...