Interweaving the Cell Cycle Machinery with Cell Differentiation

Miller, Jeffrey P.; Yeh, Nancy; Vidal, Anxo; Koff, Andrew

doi:10.4161/cc.6.23.5042

Cited by 56 publications

(50 citation statements)

References 84 publications

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“…Recent results from our laboratory indicate that VIP prevents CD3/CD28-induced p27 kip1 phosphorylation while increasing total p27 kip1 levels (our unpublished observations). Various pathways are involved in the phosphorylation of p27 kip1 , including our own formation of cdk2/cyclin E enzymatic complex and the activation of the Ras-MAPK and PI3K-Akt pathways (41,42,54,55). Our study demonstrates that VIP decreases the expression of cyclin E, and another recent study demonstrated the inhibition of the Ras-ERK1/2 and PI3K-Akt pathways by VIP in human activated T cells (our unpublished observations).…”

Section: Peripheral Cd4supporting

confidence: 54%

“…In agreement with this, both cyclin D-cdk4 and cyclinE-cdk2 activities are impaired in VIP-tolerant T cells, due to a reduced expression of cyclins D3 and E and up-regulation of the cdk inhibitor p27 kip1 . Previous studies have shown that the cell cycle inhibitor p27 kip1 acts during the late G 1 phase by binding and inhibiting cdk2-cyclin E/A complexes (41). Upon stimulation, T cells can only progress through the cell cycle when p27 kip1 is dissociated from the cdk2-cyclin E/A complexes.…”

Section: Peripheral Cd4mentioning

confidence: 99%

“…Upon stimulation, T cells can only progress through the cell cycle when p27 kip1 is dissociated from the cdk2-cyclin E/A complexes. This is in general achieved by ubiquitination and degradation of p27 kip1 , which is preceded by phosphorylation of p27 kip1 (41,42). Indeed, anergic and tolerant T cells are characterized by impaired degradation of p27 kip1 and other tolerance strategies pointed out to p27 kip1 as a critical target of anergy (24 -26).…”

Section: Peripheral Cd4mentioning

confidence: 99%

See 2 more Smart Citations

Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide

Pozo

Anderson

González‐Rey

2009

The Journal of Immunology

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T regulatory cells (Tregs) are instrumental in the maintenance of immunological tolerance. Although Treg-based immunotherapy proved successful in preclinical autoimmunity and transplantation, factors involved in the generation of human Ag-specific Tregs are poorly known. In this study, we show that treatment of human CD4+CD25− T cells with the cytokine-like vasoactive intestinal peptide (VIP) during in vitro stimulation induces an anergic FoxP3+CD4+CD25high T cell subset displaying potent regulatory activities against allospecific effector T cells, irrespective of the presence of naturally occurring Tregs. VIP-tolerant T cells are characterized by incapability to progress to S phase of cell cycle during stimulation with HLA-disparate APCs by negatively affecting the synthesis of cyclins D3 and E, the activation of cyclin-dependent kinases (cdk)2 and cdk4, and the down-regulation of the cdk inhibitor p27kip1. VIP interaction with the type 1 VIP receptor and subsequent activation of cAMP/protein kinase A pathway play a major role in all these effects. Moreover, VIP-tolerant T cells protect against acute graft-vs-host disease in a mouse model of allogeneic bone marrow transplantation. The infusion of VIP-tolerant T cells together with the graft significantly reduces the clinical signs and mortality rate typical of the graft-vs-host disease. These effects are mediated by impairing allogeneic haplotype-specific responses of donor CD4+ cells in the transplanted animals. Our results suggest that including alloantigen-specific VIP-generated Tregs may be a valuable tool in therapeutic interventions to promote immunotolerance toward allogeneic grafts and to reduce the need of general immunosuppressive drugs.

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Section: Peripheral Cd4supporting

confidence: 54%

Section: Peripheral Cd4mentioning

confidence: 99%

Section: Peripheral Cd4mentioning

confidence: 99%

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Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide

Pozo

Anderson

González‐Rey

2009

The Journal of Immunology

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“…Sustained c-Myc drives increased cell size along with persistent cell cycling and the attendant demand for increased energy production; the absence of PARP14 abrogated this increased size of B lineage-committed Eμ-myc cells. Developmental progression may require being able to exit the cell cycle (44), so it is tempting to speculate that the limitation in glycolysis prevented constant cycling, thereby allowing pre-B cells to mature. In addition, it is intriguing that bone marrow pre-B cells appeared more resistant to inhibition of glycolysis than their more mature IgM + progeny (45).…”

Section: Discussionmentioning

confidence: 99%

Glycolytic rate and lymphomagenesis depend on PARP14, an ADP ribosyltransferase of the B aggressive lymphoma (BAL) family

Cho¹,

Ahn²,

Bhargava

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

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Poly(ADP-ribose)polymerase (PARP)14-a member of the B aggressive lymphoma (BAL) family of macrodomain-containing PARPs-is an ADP ribosyltransferase that interacts with Stat6, enhances induction of certain genes by IL-4, and is expressed in B lymphocytes. We now show that IL-4 enhancement of glycolysis in B cells requires PARP14 and that this process is central to a role of PARP14 in IL-4-induced survival. Thus, enhancements of AMP-activated protein kinase activity restored both IL-4-induced glycolytic activity in Parp14 −/− B cells and prosurvival signaling by this cytokine. Suppression of apoptosis is central to B-lymphoid oncogenesis, and elevated macro-PARP expression has been correlated with lymphoma aggressiveness. Strikingly, PARP14 deficiency delayed B lymphomagenesis and reversed the block to B-cell maturation driven by the Myc oncogene. Collectively, these findings reveal links between a mammalian ADP ribosyltransferase, cytokine-regulated metabolic activity, and apoptosis; show that PARP14 influences Myc-induced oncogenesis; and suggest that the PARP14-dependent capacity to increase cellular metabolic rates may be an important determinant of lymphoma pathobiology.

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“…This is achieved through the interplay between positive and negative regulators of the cell cycle that are controlled by both cell-autonomous and nonautonomous mechanisms of gene expression Miller et al, 2007). Integrins provide an example of multimodular receptors that, depending on their αβ heterodimeric composition, can function as highly specialized transducers of extracellular cues capable of activating outside-in signaling pathways ultimately affecting cellular decisions.…”

Section: Research Article Integrins In Islet Developmentmentioning

confidence: 99%

β1 integrin is a crucial regulator of pancreatic β-cell expansion

et al. 2013

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SUMMARYDevelopment of the endocrine compartment of the pancreas, as represented by the islets of Langerhans, occurs through a series of highly regulated events encompassing branching of the pancreatic epithelium, delamination and differentiation of islet progenitors from ductal domains, followed by expansion and three-dimensional organization into islet clusters. Cellular interactions with the extracellular matrix (ECM) mediated by receptors of the integrin family are postulated to regulate key functions in these processes. Yet, specific events regulated by these receptors in the developing pancreas remain unknown. Here, we show that ablation of the β1 integrin gene in developing pancreatic β-cells reduces their ability to expand during embryonic life, during the first week of postnatal life, and thereafter. Mice lacking β1 integrin in insulin-producing cells exhibit a dramatic reduction of the number of β-cells to only ~18% of wild-type levels. Despite the significant reduction in β-cell mass, these mutant mice are not diabetic. A thorough phenotypic analysis of β-cells lacking β1 integrin revealed a normal expression repertoire of β-cell markers, normal architectural organization within islet clusters, and a normal ultrastructure. Global gene expression analysis revealed that ablation of this ECM receptor in β-cells inhibits the expression of genes regulating cell cycle progression. Collectively, our results demonstrate that β1 integrin receptors function as crucial positive regulators of β-cell expansion.

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Interweaving the Cell Cycle Machinery with Cell Differentiation

Cited by 56 publications

References 84 publications

Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide

Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide

Glycolytic rate and lymphomagenesis depend on PARP14, an ADP ribosyltransferase of the B aggressive lymphoma (BAL) family

β1 integrin is a crucial regulator of pancreatic β-cell expansion

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