Calcineurin Regulates Cyclin D1 Accumulation in Growth-stimulated Fibroblasts

Calcium (Ca2+) and calmodulin (CaM) are required for progression of mammalian cells from quiescence into S phase. In multiple cell types, cyclosporin A causes a G1 cell cycle arrest, implicating the serine/threonine phosphatase calcineurin as one Ca2+/CaM-dependent enzyme required for G1 transit. Here, we show, in diploid human fibroblasts, that cyclosporin A arrested cells in G1 before cyclin D/cdk4 complex activation and retinoblastoma hyperphosphorylation. This arrest occurred in early G1 with low levels of cyclin D1 protein. Because cyclin D1 mRNA was induced normally in the cyclosporin A-treated cells, we analyzed the half-life of cyclin D1 in the presence of cyclosporin A and found no difference from control cells. However, cyclosporin A treatment dramatically reduced cyclin D1 protein synthesis. Although these pharmacological experiments suggested that calcineurin regulates cyclin D1 synthesis, we evaluated the effects of overexpression of activated calcineurin on cyclin D1 synthesis. In contrast to the reduction of cyclin D1 with cyclosporin A, ectopic expression of calcium/calmodulin-independent calcineurin promoted synthesis of cyclin D1 during G1 progression. Therefore, calcineurin is a Ca2+/CaM-dependent target that regulates cyclin D1 accumulation in G1.

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Cyclin D1 Protein Tissue Detection in Laryngeal Cancer

ORL ◽

10.1159/000090041 ◽

2005 ◽

Vol 67 (6) ◽

pp. 319-325 ◽

Cited By ~ 3

Author(s):

John V. Segas ◽

Andreas C. Lazaris ◽

Thomas P. Nikolopoulos ◽

Nikolaos G. Kavantzas ◽

Irene E. Lendari ◽

...

Keyword(s):

Cyclin D1 ◽

Laryngeal Cancer ◽

D1 Protein ◽

Cyclin D1 Protein

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mTOR function in skeletal muscle hypertrophy: increased ribosomal RNA via cell cycle regulators

AJP Cell Physiology ◽

10.1152/ajpcell.00165.2005 ◽

2005 ◽

Vol 289 (6) ◽

pp. C1457-C1465 ◽

Cited By ~ 104

Author(s):

Gustavo A. Nader ◽

Thomas J. McLoughlin ◽

Karyn A. Esser

Keyword(s):

Cell Cycle ◽

Protein Expression ◽

Cyclin D1 ◽

Ribosomal Rna ◽

Molecular Mechanisms ◽

D1 Protein ◽

Rna Content ◽

Cyclin D1 Protein ◽

Rb Phosphorylation ◽

Myotube Hypertrophy

The purpose of this study was to identify the potential downstream functions associated with mammalian target of rapamycin (mTOR) signaling during myotube hypertrophy. Terminally differentiated myotubes were serum stimulated for 3, 6, 12, 24, and 48 h. This treatment resulted in significant myotube hypertrophy (protein/DNA) and increased RNA content (RNA/DNA) with no changes in DNA content or indices of cell proliferation. During myotube hypertrophy, the increase in RNA content was accompanied by an increase in tumor suppressor protein retinoblastoma (Rb) phosphorylation and a corresponding increase in the availability of the ribosomal DNA transcription factor upstream binding factor (UBF). Serum stimulation also induced an increase in cyclin D1 protein expression in the differentiated myotubes with a concomitant increase in cyclin D1-dependent cyclin-dependent kinase (CDK)-4 activity toward Rb. The increases in myotube hypertrophy and RNA content were blocked by rapamycin treatment, which also prevented the increase in cyclin D1 protein expression, CDK-4 activity, Rb phosphorylation, and the increase in UBF availability. Our findings demonstrate that activation of mTOR is necessary for myotube hypertrophy and suggest that the role of mTOR is in part to modulate cyclin D1-dependent CDK-4 activity in the regulation of Rb and ribosomal RNA synthesis. On the basis of these results, we propose that common molecular mechanisms contribute to the regulation of myotube hypertrophy and growth during the G1 phase of the cell cycle.

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Functions of p53 in pluripotent stem cells

Protein & Cell ◽

10.1007/s13238-019-00665-x ◽

2019 ◽

Vol 11 (1) ◽

pp. 71-78 ◽

Cited By ~ 10

Author(s):

Xuemei Fu ◽

Shouhai Wu ◽

Bo Li ◽

Yang Xu ◽

Jingfeng Liu

Keyword(s):

Stem Cells ◽

Pluripotent Stem Cells ◽

Mammalian Cells ◽

Genomic Stability ◽

Cell Types ◽

The Body ◽

Great Promise ◽

Primary Role ◽

Cycle Arrest ◽

Clinical Potential

Abstract Pluripotent stem cells (PSCs) are capable of unlimited self-renewal in culture and differentiation into all functional cell types in the body, and thus hold great promise for regenerative medicine. To achieve their clinical potential, it is critical for PSCs to maintain genomic stability during the extended proliferation. The critical tumor suppressor p53 is required to maintain genomic stability of mammalian cells. In response to DNA damage or oncogenic stress, p53 plays multiple roles in maintaining genomic stability of somatic cells by inducing cell cycle arrest, apoptosis, and senescence to prevent the passage of genetic mutations to the daughter cells. p53 is also required to maintain the genomic stability of PSCs. However, in response to the genotoxic stresses, a primary role of p53 in PSCs is to induce the differentiation of PSCs and inhibit pluripotency, providing mechanisms to maintain the genomic stability of the self-renewing PSCs. In addition, the roles of p53 in cellular metabolism might also contribute to genomic stability of PSCs by limiting oxidative stress. In summary, the elucidation of the roles of p53 in PSCs will be a prerequisite for developing safe PSC-based cell therapy.

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Immunohistochemical Analysis of Cyclin D1 Protein in Hematopoietic Neoplasms with Special Reference to Mantle Cell Lymphoma

Japanese Journal of Cancer Research ◽

10.1111/j.1349-7006.1994.tb02940.x ◽

1994 ◽

Vol 85 (12) ◽

pp. 1270-1279 ◽

Cited By ~ 28

Author(s):

Shigeo Nakamura ◽

Masao Seto ◽

Shogo Banno ◽

Susumu Suzuki ◽

Takashi Koshikawa ◽

...

Keyword(s):

Special Reference ◽

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

D1 Protein ◽

Immunohistochemical Analysis ◽

Cyclin D1 Protein ◽

Mantle Cell

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Adenoma Growth Stimulation by the trans-10, cis-12 Isomer of Conjugated Linoleic Acid (CLA) Is Associated with Changes in Mucosal NF-κB and Cyclin D1 Protein Levels in the Min Mouse

Journal of Nutrition ◽

10.1093/jn/133.6.1943 ◽

2003 ◽

Vol 133 (6) ◽

pp. 1943-1948 ◽

Cited By ~ 33

Author(s):

Johanna Rajakangas ◽

Samar Basu ◽

Irma Salminen ◽

Marja Mutanen

Keyword(s):

Linoleic Acid ◽

Cyclin D1 ◽

Conjugated Linoleic Acid ◽

D1 Protein ◽

Growth Stimulation ◽

Protein Levels ◽

Cyclin D1 Protein

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Overexpression of cyclin D1 protein in pancreatic endocrine tumors

Gastroenterology ◽

10.1016/s0016-5085(98)81810-6 ◽

1998 ◽

Vol 114 ◽

pp. A448

Author(s):

DC Chung ◽

SB Brown ◽

F Graeme-Cook ◽

AL Warshaw ◽

M Seto ◽

...

Keyword(s):

Cyclin D1 ◽

D1 Protein ◽

Endocrine Tumors ◽

Pancreatic Endocrine Tumors ◽

Cyclin D1 Protein

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Gamma Interferon and Cadmium Treatments Modulate Eukaryotic Initiation Factor 4E-Dependent mRNA Transport of Cyclin D1 in a PML-Dependent Manner

Molecular and Cellular Biology ◽

10.1128/mcb.22.17.6183-6198.2002 ◽

2002 ◽

Vol 22 (17) ◽

pp. 6183-6198 ◽

Cited By ~ 34

Author(s):

Ivan Topisirovic ◽

Allan D. Capili ◽

Katherine L. B. Borden

Keyword(s):

Cyclin D1 ◽

D1 Protein ◽

Nuclear Bodies ◽

Initiation Factor ◽

Eukaryotic Initiation Factor ◽

Mrna Transport ◽

Protein Levels ◽

Eukaryotic Initiation Factor 4E ◽

Cadmium Treatment ◽

Cyclin D1 Protein

ABSTRACT The eukaryotic initiation factor 4E (eIF4E), when dysregulated, transforms cells. A substantial fraction of eIF4E forms nuclear bodies that colocalize with those associated with the promyelocytic leukemia protein PML. Overexpression studies indicate that nuclear eIF4E promotes the transport of cyclin D1 mRNA from the nucleus to the cytoplasm and that PML is a key negative regulator of this function. Since previous studies used overexpression methods, the physiological relevance of eIF4E mRNA transport function or its interaction with PML remained unknown. Therefore, we monitored whether eIF4E-dependent transport could be modulated in response to environmental conditions. Here we report that cadmium treatment, which disperses PML nuclear bodies, leaves eIF4E bodies intact, leading to increased transport of cyclin D1 mRNA and increased cyclin D1 protein levels. Removal of cadmium allows PML to reassociate with eIF4E nuclear bodies, leading to decreased cyclin D1 transport and reduced cyclin D1 protein levels. In contrast, we show that treating cells with interferon increased the levels of PML protein at the PML-eIF4E nuclear body, leading to nuclear retention of cyclin D1 transcripts and reduced cyclin D1 protein levels. Neither interferon nor cadmium treatment altered cyclin D1 levels in PML−/− cells. Consistently, overexpression of a series of PML and eIF4E mutant proteins established that PML eIF4E interaction is required for the observed effects of cadmium and interferon treatment. The present study provides the first evidence that physiological factors modulate the mRNA transport functions of eIF4E and that this regulation is PML dependent.

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Iron chelation regulates cyclin D1 expression via the proteasome: a link to iron deficiency–mediated growth suppression

Blood ◽

10.1182/blood-2006-10-047753 ◽

2006 ◽

Vol 109 (9) ◽

pp. 4045-4054 ◽

Cited By ~ 95

Author(s):

Effie Nurtjahja-Tjendraputra ◽

Dong Fu ◽

Juanita M. Phang ◽

Des R. Richardson

Keyword(s):

Cell Cycle ◽

Cyclin D1 ◽

Cell Cycle Control ◽

D1 Protein ◽

Iron Chelation ◽

Growth Suppression ◽

Dependent Manner ◽

Critical Function ◽

Cyclin D1 Protein

Abstract Iron (Fe) plays an important role in proliferation, and Fe deficiency results in G1/S arrest. Despite this, the precise role of Fe in cell-cycle control remains unclear. Cyclin D1 plays a critical function in G1 progression by interacting with cyclin-dependent kinases. Previously, we examined the effect of Fe depletion on the expression of cell-cycle control molecules and identified a marked decrease in cyclin D1 protein, although the mechanism involved was unknown. In this study, we showed that cyclin D1 was regulated posttranscriptionally by Fe depletion. Iron chelation of cells in culture using desferrioxamine (DFO) or 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) decreased cyclin D1 protein levels after 14 hours and was rescued by the addition of Fe. Cyclin D1 half-life in control cells was 80 ± 15 minutes (n = 5), while in chelator-treated cells it was significantly (P < .008) decreased to 38 ± 3 minutes (n = 5). Proteasomal inhibitors rescued the Fe chelator–mediated decrease in cyclin D1 protein, suggesting the role of the proteasome. In Fe-replete cells, cyclin D1 was degraded in an ubiquitin-dependent manner, while Fe depletion induced a ubiquitin-independent pathway. This is the first report linking Fe depletion–mediated growth suppression at G1/S to a mechanism inducing cyclin D1 proteolysis.

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