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At least 19 recordsLinked to original sources
PubMed2002

Cell cycle progression of chronic lymphocytic leukemia cells is controlled by cyclin D2, cyclin D3, cyclin-dependent kinase (cdk) 4 and the cdk inhibitor p27.

B-CLL cells are arrested in G0/early G1 phase of the cell cycle and are characterized by a marked hyporesponsiveness towards a variety of polyclonal B cell activators. We have previously demonstrated that costimulation with CpG-ODN and IL-2 can overcome this proliferative defect. Cyclin D3 is the principal D-type cyclin which mediates G1 progression in normal B cells, but in B-CLL cells both cyclin D2 and cyclin D3, were strongly upregulated upon stimulation. Both cyclins were associated with cdk4 but not with cdk6, which is the catalytic partner of D-type cyclins in normal B cells. Moreover, immune complexes consisting of cyclin D2 and cdk4 or cyclin D3 and cdk4 were both functional and phosphorylated the RB protein in vitro. The cell cycle inhibitor p27 plays a pivotal role in cell cycle progression of B lymphocytes and has been shown to be overexpressed in B-CLL cells. P27 was rapidly downregulated in B-CLL cells even when stimulated with a non-CpG-ODN or IL-2 alone, while only moderate regulation could be observed in normal B cells. Taken together, our findings demonstrate that regulation of early cell cycle progression differs between B-CLL cells and normal B cells. These findings do not only contribute to the understanding of B-CLL pathophysiology, but might ultimately lead to the identification of new therapeutic targets.

Apoptosis↗
PubMed1996

Functional analysis of the human cyclin D2 and cyclin D3 promoters.

The D-type cyclins promote progression through the G1 phase of the cell cycle and may provide a link between growth factors and the cell cycle machinery. We determined the nucleotide sequence of the 5'-flanking region of the human cyclin D2 and cyclin D3 genes and identified the transcription start sites. Analysis of the upstream sequences required for transcription of the cyclin D2 and cyclin D3 genes in continuously dividing cells revealed marked differences in their regulatory elements. In the cyclin D2 gene positive elements were localized between positions -306 and -114 relative to the ATG codon at +1. Additional positive elements were localized between -444 and -345, whereas sequences that reduced transcription were identified between nucleotides -1624 and -892. In the cyclin D3 gene all of the positive elements required for maximal transcription were localized between nucleotides -366 and -167, and no negative elements were found. The activities of a reporter gene linked to the upstream regulatory sequences of the cyclin D2 gene but not the cyclin D3 gene were induced when starved cells were serum stimulated. This suggests that although the abundance of both the cyclin D2 and cyclin D3 mRNAs is increased by serum stimulation, only the cyclin D2 gene is up-regulated at the transcriptional level. Sequences between nucleotides -306 and -1624 of the cyclin D2 gene were necessary for serum inducibility.

Animals↗
PubMed2006

Cyclin D2 and cyclin D3 play opposite roles in mouse skin carcinogenesis.

D-type cyclins are components of the cell-cycle engine that link cell signaling pathways and passage throughout G1 phase. We previously described the effects of overexpression cyclin D1, D2 or D3 in mouse epidermis and tumor development. We now asked whether cyclin D2 and/or cyclin D3 play a relevant role in ras-dependent tumorigenesis. Here, we described the effect of cyclin D3 and cyclin D2 overexpression in mouse skin tumor development. Notably, overexpression of cyclin D3 results in reduced tumor development and malignant progression to squamous cell carcinomas (SCC). Biochemical analysis of keratinocytes shows that overexpression of cyclin D3 results in strong reduction of cyclin D2 and its associated kinase activity. Furthermore, we found that reinstatement of cyclin D2 level in the cyclin D3/cyclin D2 bigenic mice results in a complete reversion of the inhibitory action of cyclin D3. Supporting these results, ablation of cyclin D2 results in reduced tumorigenesis and malignant progression. On the other hand, overexpression of cyclin D2 results in an increased number of papillomas and malignant progression. We conclude that cyclin D3 and cyclin D2 play opposite roles in mouse skin tumor development and that the suppressive activity of cyclin D3 is associated with cyclin D2 downregulation.

Animals↗
PubMed2006

Disruption of cyclin D3 blocks proliferation of normal B-1a cells, but loss of cyclin D3 is compensated by cyclin D2 in cyclin D3-deficient mice.

Peritoneal B-1a cells differ from splenic B-2 cells in the molecular mechanisms that control G(0)-S progression. In contrast to B-2 cells, cyclin D2 is up-regulated in a rapid and transient manner in phorbol ester (PMA)-stimulated B-1a cells, whereas cyclin D3 does not accumulate until late G(1) phase. This nonoverlapping expression of cyclins D2 and D3 suggests distinct functions for these proteins in B-1a cells. To investigate the contribution of cyclin D3 in the proliferation of B-1a cells, we transduced p16(INK4a) peptidyl mimetics (TAT-p16) into B-1a cells before cyclin D3 induction to specifically block cyclin D3-cyclin-dependent kinase 4/6 assembly. TAT-p16 inhibited DNA synthesis in B-1a cells stimulated by PMA, CD40L, or LPS as well as endogenous pRb phosphorylation by cyclin D-cyclin-dependent kinase 4/6. Unexpectedly, however, cyclin D3-deficient B-1a cells proliferated in a manner similar to wild-type B-1a cells following PMA or LPS stimulation. This was due, at least in part, to the compensatory sustained accumulation of cyclin D2 throughout G(0)-S progression. Taken together, experiments in which cyclin D3 was inhibited in real time demonstrate the key role this cyclin plays in normal B-1a cell mitogenesis, whereas experiments with cyclin D3-deficient B-1a cells show that cyclin D2 can compensate for cyclin D3 loss in mutant mice.

Amino Acid Sequence↗
PubMed2006

Regulation of cyclin D2 and the cyclin D2 promoter by protein kinase A and CREB in lymphocytes.

Lymphocyte proliferation is key to the regulation of the immune system. Cyclin D2 is the first cell cycle protein induced following stimulation through the T-cell receptor, the B-cell receptor or cytokines. The promoter of this cyclin integrates a diverse range of signals. Through investigating the regulation of this promoter by interleukin-2 and phosphatidylinositol 3-kinase, we have identified a role for the transcription factor CREB, cAMP response element-binding protein. Mutation of the CREB-binding site reduced cyclin D2 promoter activity 5-10-fold. CREB-1 is phosphorylated at serine 133, a critical site for activity, in both T cells and Epstein-Barr virus immortalized B cells. The introduction of an S133A mutant of CREB-1 reduces IL-2 induction of cyclin D2 promoter activity, demonstrating a role for this phosphorylation site in promoter activity. Two inhibitors of protein kinase A reduce lymphocyte proliferation and CREB-1 phosphorylation. This study demonstrates that the cyclin D2 promoter is capable of being regulated by PI3K and CREB and identifies CREB-1 and protein kinase A as potential targets for altering lymphocyte proliferation.

B-Lymphocytes↗
PubMed2002

Early cycling-independent changes to p27, cyclin D2, and cyclin D3 in differentiating mouse embryonal carcinoma cells.

Changes to cell cycle-regulating machinery that occur during differentiation of cells are thought to be responsible mostly for withdrawal from cycling. Here, embryonal carcinoma (EC) cell lines were found that differ in their basal levels of p27 inhibitor of cyclin-dependent kinases but not in their growth rates, distribution of cells in phases of cell cycle, and their ability to differentiate. High basal levels of p27 did not substitute for up-regulation of p27 that in EC cells normally occurs early after entering a differentiation pathway. Under both standard and differentiation-supporting culture conditions, variances in the levels of p27 were strictly followed by variances in the levels of cyclins D2 and D3. In EC cells genetically manipulated to overexpress p27 protein, cyclin D3 became up-regulated and vice versa. Supposedly, titration of p27 by D-type cyclins, which prevents its inhibitory action toward cyclin-dependent kinase 2, allows for the maintenance of elevated p27 in proliferating EC cells. Increased levels of p27 in early embryonal cells thus may, at least in certain phases of embryo development, serve a differentiation-associated, rather than proliferation-associated, function.

Animals↗
PubMed2002

Functional analysis of cyclin D2 and p27(Kip1) in cyclin D2 transgenic mouse mammary gland during development.

Two mammary gland phenotypes were detected in pregnant MMTV-cyclin D2 transgenic mice; line D2-53 exhibited a lack of alveologenesis and failure to nurse, whereas line D2-58 featured a reduction in alveologenesis, but retained normal nursing behavior. In pregnant mammary glands, cyclin D2 protein levels were twofold (P<0.107) and 3.8-fold (P<0.0076) higher in line D2-58 and D2-53, respectively, compared to wild type. Concomitantly with the increase in cyclin D2 was a fivefold decrease in cyclin D1 hyper-phosphorylated isoform in mammary glands of pregnant cyclin D2-58 mice. Because cyclin D1 is a critical molecule in normal mammary lobuloalveolar development, these data suggest that overexpression of cyclin D2 may block mammary lobuloalveolar development through inhibition of cyclin D1 phosphorylation. During mammary gland development, p27(kip1) protein level oscillated in a similar profile in wild type and cyclin D2 transgenic mice, but was consistently higher in the cyclin D2 mice suggesting that p27(kip1) functions downstream of cyclin D2. The ratio of p27(kip1)-cdk4/p27(kip1)-cdk2 was 6.5-fold (P<0.0003) higher in cyclin D2 mammary glands compared to wild type in pregnant animals. This ratio reversed to 2.2-fold (P<0.005) higher in wild type compared to cyclin D2 mammary glands in involution suggesting that overexpression of cyclin D2 moderately induced apoptosis during pregnancy but accelerated involution. Collectively, the effects of cyclin D2 overexpression on mammary gland development during pregnancy and involution are attributed to two major factors, altered p27(kip1) protein level and inhibition of cyclin D1 phosphorylation.

Animals↗
PubMed1998

G1-phase regulators, cyclin D1, cyclin D2, and cyclin D3: up-regulation at gastrulation and dynamic expression during neurulation.

Gastrulation in rodents is associated with an increase in the rate of growth and with the start of differentiation within the embryo proper. In an effort to understand the role played by the cell cycle control in these processes, expression of cyclin D1, D2, and D3--three major positive regulators of the G1/S transition--has been investigated by in situ hybrization and RT-PCR. Cyclin D1 and D2 transcripts are first detected in the epiblast at gastrulation, when a proliferative burst occurs, and subsequently in its differentiated derivatives within the embryo proper, indicating that activation of their expression takes place prior to the differentiation of epiblast progenitors. In contrast, cyclin D3 transcript is undetectable in the epiblast itself and its expression is activated exclusively in extraembryonic tissues of both epiblast and trophoblast origin. During neurulation, expression of each cyclin D RNA is dynamically regulated along the anterior-posterior axis. In the hindbrain, cyclin D1 and D2 show distinct segment-specific restricted expression and this pattern is conserved between mouse and chick. These results strongly suggest that D-type cyclins act as developmental regulators.

Animals↗
PubMed1998

Proliferation-independent induction of macrophage cyclin D2, and repression of cyclin D1, by lipopolysaccharide.

D-type cyclins are induced in response to mitogens and are essential and rate-limiting for G1 phase progression in normal mammalian cells. Macrophages proliferating in response to colony-stimulating factor-1 (CSF-1) express cyclin D1 and to a lesser extent cyclin D2 but not cyclin D3. Previously we showed that the macrophage-activating agent lipopolysaccharide (LPS) blocks CSF-1-induced proliferation and cyclin D1 expression in macrophages. Here we report upon the effect of LPS on expression of cyclin D2 in normal mouse bone marrow-derived macrophages (BMM). Unexpectedly we found that this anti-mitogen raised levels of CSF-1-stimulated cyclin D2 mRNA and protein. Furthermore, LPS alone induced cyclin D2 but not cyclin D1. Inhibition of the MEK/ERK (MAPK/ERK kinase/extracellular signal-regulated kinase) mitogen-activated protein kinase pathway repressed LPS-induced cyclin D2 mRNA, whereas inhibition of the p38 mitogen-activated protein kinase enhanced expression. However, in contrast to cyclin D1, cyclin D2 in bone marrow-derived macrophages did not appear to be regulated by protein kinase A pathways. The present data (a) show elevation of a D-type cyclin in the absence of proliferation, (b) demonstrate inverse regulation of two distinct D-type cyclins under identical conditions, and (c) suggest that cyclin D2 plays a role in macrophage activation by LPS.

Animals↗
PubMed1999

Cyclin D2, but not cyclin D1, overexpression closely correlates with gastric cancer progression and prognosis.

Expression of cyclins D1 and D2, as well as cyclin-dependent kinase 4 (cdk4), was investigated by means of immunohistochemistry in 455 gastric cancer cases. Additional western blotting was performed for four breast cancer and four gastric cancer cell lines and 35 fresh frozen gastric cancer samples, to confirm the cyclin D1, D2, and cdk4 data. Cyclin D1 was restricted to the nucleus of cancer cells with a few exceptions, whereas cyclin D2 was present in both cell compartments, but predominantly in the cytoplasm. Cdk4 was intermediately expressed. Cyclin D1 was overexpressed in 93 cases (20.4 per cent) and cyclin D2 in 105 (23.0 per cent). In the cyclin D2 cases, this correlated with greater age (p=0.0004), better differentiation (p=0.0023), greater depth of cancer invasion (p=0. 003), the presence of lymph node metastasis (p=0.0014), vascular invasion by cancer cells (p< 0.0001), and poor prognosis (p< 0.0001), while cyclin D1 did not correlate with any of these except age (p=0.00193). Multivariate analysis revealed cyclin D2 overexpression to be an independent prognostic factor, in addition to depth of cancer invasion and lymph node status. Cdk4 overexpression was linked to cyclin D1, but not cyclin D2 overexpression. The results indicate that cyclin D2 up-regulation plays an important role in the progression and prognosis of gastric cancer independently of cdk4, whereas cyclin D1 overexpression does not.

Adult↗
PubMed2005

Genetic replacement of cyclin D1 function in mouse development by cyclin D2.

D cyclins (D1, D2, and D3) are components of the core cell cycle machinery in mammalian cells. It is unclear whether each of the D cyclins performs unique, tissue-specific functions or the three proteins have virtually identical functions and differ mainly in their pattern of expression. We previously generated mice lacking cyclin D1, and we observed that these animals displayed hypoplastic retinas and underdeveloped mammary glands and a presented developmental neurological abnormality. We now asked whether the specific requirement for cyclin D1 in these tissues reflected a unique pattern of D cyclin expression or the presence of specialized functions for cyclin D1 in cyclin D1-dependent compartments. We generated a knock-in strain of mice expressing cyclin D2 in place of D1. Cyclin D2 was able to drive nearly normal development of retinas and mammary glands, and it partially replaced cyclin D1's function in neurological development. We conclude that the differences between these two D cyclins lie mostly in the tissue-specific pattern of their expression. However, we propose that subtle differences between the two D cyclins do exist and they may allow D cyclins to function in a highly optimized fashion. We reason that the acquisition of multiple D cyclins may allow mammalian cells to drive optimal proliferation of a diverse array of cell types.

Animals↗
PubMed1995

Structure and gene expression of avian cyclin D2.

Avian cyclin D2 (Cyl D2)-encoding cDNA clones were isolated from a chicken UG9 T-cell lambda gt10 library. Sequence analysis revealed a high degree of sequence conservation with both the mouse and human Cyl D2, and somewhat lower similarity with the mouse and human Cyl D1 and D3. The homology is highest between species in the Cyl-box domain which is well conserved among human, mouse and chicken. A single 6.0-kb CYL2 mRNA is produced in both avian B- and T-cells, as expected.

Amino Acid Sequence↗
PubMed2001

Regulation of cyclin D2 gene expression by the Myc/Max/Mad network: Myc-dependent TRRAP recruitment and histone acetylation at the cyclin D2 promoter.

Myc oncoproteins promote cell cycle progression in part through the transcriptional up-regulation of the cyclin D2 gene. We now show that Myc is bound to the cyclin D2 promoter in vivo. Binding of Myc induces cyclin D2 expression and histone acetylation at a single nucleosome in a MycBoxII/TRRAP-dependent manner. Down-regulation of cyclin D2 mRNA expression in differentiating HL60 cells is preceded by a switch of promoter occupancy from Myc/Max to Mad/Max complexes, loss of TRRAP binding, increased HDAC1 binding, and histone deacetylation. Thus, recruitment of TRRAP and regulation of histone acetylation are critical for transcriptional activation by Myc.

Acetylation↗
PubMed2006

D cyclins in CD5+ B-cell lymphoproliferative disorders: cyclin D1 and cyclin D2 identify diagnostic groups and cyclin D1 correlates with ZAP-70 expression in chronic lymphocytic leukemia.

We analyzed protein expression of cyclin D1, cyclin D2, and cyclin D3 using high-resolution enzymatic amplification staining and flow cytometry in the neoplastic cells from 80 patients with CD5+ B-cell lymphoproliferative disorders. The D cyclins were expressed differentially in chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), and mantle cell lymphoma (MCL) with strong staining of cyclin D1 and D2 in MCL, strong staining of cyclin D1 but weak staining of cyclin D2 in 4 of 5 PLLs, and low-level staining for both cyclins in most CLLs. No correlation between cyclin D1 and D2 and growth rates or CD38 expression was observed. However, cyclin D1 levels were significantly higher in ZAP-70+ CLL cases, although no association between ZAP-70 and cyclin D2 was detected. The results indicate that flow cytometric analysis of D cyclins may help in classification of CD5+ B-cell lymphoproliferative disorders.

ADP-ribosyl Cyclase 1↗
PubMed2003

Follicle stimulating hormone-induced DNA synthesis in the granulosa cells of hamster preantral follicles involves activation of cyclin-dependent kinase-4 rather than cyclin d2 synthesis.

Although cyclin D2 mRNA synthesis precedes gonadotropin-induced DNA synthesis in quiescent granulosa cells in culture, it is unclear whether a similar mechanism exists for the granulosa cells of growing preantral follicles in cyclic animals. The objective was to evaluate whether the synthesis of cyclin D2 protein was a prerequisite for FSH-induced DNA synthesis in the granulosa cells of intact preantral follicles of cyclic hamsters. Preantral follicles from cyclic hamsters were cultured in the presence or absence of FSH, and cell cycle parameters were examined. FSH stimulated cyclin-dependent kinase (CDK)-4 activity by 2 h and DNA synthesis by 4 h without altering the levels of cyclin D2 in the granulosa cells. The FSH effect was mimicked by epidermal growth factor administered in vivo. Although FSH increased the levels of cyclin D2 mRNA, it also stimulated the degradation of cyclin D2 as well as p27(Kip1) and p19(INK4) proteins. FSH activation of CDK4 was mediated by cAMP and ERK-1/2. In contrast to granulosa cells in intact follicles, FSH or cAMP significantly increased cyclin D2 protein levels in cultured granulosa cells but failed to induce DNA synthesis. Collectively, these data suggest that granulosa cells of preantral follicles, which are destined to enter the S phase during the estrous cycle, contain necessary amounts of cyclin D2 and other G1 phase components. FSH stimulation results in the formation and activation of the cyclin D2/CDK4 complex leading to DNA synthesis. This mechanism may be necessary for rapid movement of follicles from preantral to antral stages during the short duration of the murine estrous cycle.

Animals↗
PubMed1999

Transcriptional up-regulation of the cyclin D2 gene and acquisition of new cyclin-dependent kinase partners in human T-cell leukemia virus type 1-infected cells.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis. Tax(1) is a 40-kDa phosphoprotein, predominantly localized in the nucleus of the host cell, which functions to transactivate both viral and cellular promoters. It seems likely that HTLV-1, through expression of the viral regulatory protein Tax(1), provides some initial alteration in cell metabolism predisposing the development of ATL. Here, we demonstrate that HTLV-1 infection in T-cell lines and patient samples causes overexpression of an early G(1) cyclin, cyclin D2. The transcriptional up-regulation of the cyclin D2 gene is due to activation of Tax on the cyclin D2 gene. More important, we find that overexpression of cyclin D2 is accompanied by acquisition of new partners such as cyclin-dependent kinase 2 (cdk2), cdk4, and cdk6 in infected cells. This is in contrast to uninfected T cells, where cyclin D2 associates only with cdk6. Functional effects of these cyclin-cdk complexes in infected cells are shown by hyperphosphorylation of Rb and histone H1, indicators of active progression into S phase as well as changes in cellular chromatin and transcription machinery. These studies link HTLV-1 infection with changes of cellular cyclin gene expression, hence providing clues to development of T-cell leukemia.

Animals↗
PubMed2003

Cyclin D2 controls B cell progenitor numbers.

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 (CD19lo) than those from cyclin D2+/+ mice (CD19Hi). 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, S807/811. We conclude that cyclin D2 is rate-limiting for the production of B lymphoid progenitor cells whose proliferation does not depend on BCR signaling.

Animals↗
PubMed2006

Akt induces beta-cell proliferation by regulating cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity.

Proliferation is the major component for maintenance of beta-cell mass in adult animals. Activation of phosphoinositide 3-kinase/Akt-kinase pathway is a critical regulator of beta-cell mass. Pancreatic beta-cell overexpression of constitutively active Akt in mice (caAkt(Tg)) resulted in marked expansion of beta-cell mass by increase in beta-cell proliferation and size. The current studies provide new insights into the molecular mechanisms involved in beta-cell proliferation by Akt. Proliferation of beta-cells in caAkt(Tg) was associated with increased cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 (cdk4) activity. To determine the role of cdk4 in beta-cell proliferation induced by Akt, we generated caAkt(Tg) mice that were homozygous, heterozygous, or nullizygous for cdk4. The results of these studies showed that deletion of one cdk4 allele significantly reduced beta-cell expansion in caAkt(Tg) mice by decreased proliferation. CaAkt(Tg) mice deficient in cdk4 developed beta-cell failure and diabetes. These experiments suggest that Akt induces beta-cell proliferation in a cdk4-dependent manner by regulation of cyclin D1, cyclin D2, and p21 levels. These data also indicate that alteration in levels of these cell cycle components could affect the maintenance of beta-cell mass in basal states and the adaptation of beta-cells to pathological states resulting in diabetes.

Animals↗