A glucocorticoid‐induced leucine‐zipper protein, GILZ, inhibits adipogenesis of mesenchymal cells

Shi, Xing Ming; Shi, Weibin; Li, Qingnan; Song, Buer; Wan, Mei; Bai, Shuting; Cao, Xu

doi:10.1038/sj.embor.embor805

Cited by 128 publications

(135 citation statements)

References 25 publications

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“…HDACs are enzymes that play an important role in the regulation of gene expression and are best known for their role in repressing gene transcription via interaction with transcriptional repressors [Ng and Bird, 2000]. Interestingly, both HDACs and transcriptional repressors have previously been implicated in the regulation of adipocyte differentiation: HDAC-1 has been shown to associate with the C/EBPa promoter and play an important role in preventing C/EBPa expression in unstimulated preadipocytes [Wiper-Bergeron et al, 2003], while a number of transcriptional repressors have been implicated in the regulation of adipogenesis via the direct inhibition of both C/EBPa and PPARg gene expression [Tong et al, 2000;Yun et al, 2002;Banerjee et al, 2003;Shi et al, 2003]. Hence, it is tempting to speculate that one potential mechanism by which the PGF2a-calcineurin signaling pathway may inhibit adipocyte differentiation is by inducing the expression and/or activity of an HDAC-associated transcriptional repressor that is either able to directly inhibit the expression of the PPARg and C/EBPa genes, or alternatively, acts indirectly, by inhibiting the expression of a gene(s) that is normally required to promote the expression of PPARg and C/ EBPa.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin F2α inhibits adipocyte differentiation via a Gαq‐Calcium‐Calcineurin‐Dependent signaling pathway

Liu

Clipstone

2006

J of Cellular Biochemistry

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Prostaglandin F2a (PGF2a) is a potent physiological inhibitor of adipocyte differentiation, however the specific signaling pathways and molecular mechanisms involved in mediating its anti-adipogenic effects are not well understood. In the current study, we now provide evidence that PGF2a inhibits adipocyte differentiation via a signaling pathway that requires heterotrimeric G-protein Gaq subunits, the elevation of the intracellular calcium concentration ([Ca 2þ ] i ), and the activation of the Ca 2þ /calmodulin-regulated serine/threonine phosphatase calcineurin. We show that while this pathway acts to inhibit an early step in the adipogenic cascade, it does not interfere with the initial mitotic clonal expansion phase of adipogenesis, nor does it affect either the expression, DNA binding activity or differentiation-induced phosphorylation of the early transcription factor C/EBPb. Instead, we find that PGF2a inhibits adipocyte differentiation via a calcineurin-dependent mechanism that acts to prevent the expression of the critical pro-adipogenic transcription factors PPARg and C/EBPa. Furthermore, we demonstrate that the inhibitory effects of PGF2a on both the expression of PPARg and C/EBPa and subsequent adipogenesis can be attenuated by treatment of preadipocytes with the histone deacetylase (HDAC) inhibitor trichostatin A. Taken together, these results indicate that PGF2a inhibits adipocyte differentiation via a Gaq-Ca 2þ -calcineurin-dependent signaling pathway that acts to block expression of PPARg and C/EBPa by a mechanism that appears to involves an HDAC-sensitive step.

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Section: Discussionmentioning

confidence: 99%

Prostaglandin F2α inhibits adipocyte differentiation via a Gαq‐Calcium‐Calcineurin‐Dependent signaling pathway

Liu

Clipstone

2006

J of Cellular Biochemistry

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“…Isolated total RNAs from cells were applied for Northern blotting using C/EBPalpha and actin genes as probe (b). Same materials were reverse transcribed using oligo-dT and then applied for PCR using C/EBPalpha-specific primers as described in Materials and methods (Shi et al, 2003). As control, RT-PCR without template (c) was performed.…”

Section: Discussionmentioning

confidence: 99%

“…For RT-PCR, double-stranded cDNA was synthesized from 1 mg of total RNA using the cDNA Synthesis System (Roche Diagnostics, Penzberg, Germany) according to the manufacturer's instructions. PCR was performed using the primer sets described by Shi et al (2003).…”

Section: Plasmid Constructions and Establishment Of Cell Linesmentioning

confidence: 99%

FMIP controls the adipocyte lineage commitment of C2C12 cells by downmodulation of C/EBPalpha

et al. 2006

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Fms interacting protein (FMIP) is a substrate for Fms tyrosine kinase, and a nuclear/cytoplasm shuttling protein with a leucine zipper. As the phosphorylation of FMIP is observed in insulin-stimulated preadipocytes, we examined the role of FMIP in adipocyte differentiation, using the mesenchymal multipotent stem cells, C2C12 cells, that can differentiate into adipocytes, muscle cells and osteoblasts. Ectopic expression of FMIP in C2C12 impairs the adipocyte differentiation induced by treatment with insulin, dexamethasone and 3-isobutyl-1-methylxanthine. These cells exhibit muscle phenotype with multinuclear morphology. Furthermore, knockdown of endogenous FMIP expression by small interfering RNA improves adipocytic lineage commitment of C2C12 cells, while impairing muscle differentiation. Upon stimulation with insulin, CCAAT/enhancer binding protein (C/EBP)-beta, but not C/EBPalpha, is upregulated in cells expressing ectopic FMIP, whereas in FMIP knockdown cells, C/EBPalpha is constitutively expressed. Ectopic expression of C/EBPalpha counteracts the effects of FMIP, whereas C/EBPalpha knockdown partially mimics the effects of FMIP in this system. Northern blot analysis and reverse transcriptase-polymerase chain reaction study reveal that ectopic FMIP-expressing cells do not contain the polyadenylated C/EBPalpha mRNA, but contain the C/EBPalpha pre-mRNA, suggesting that FMIP plays a role in RNA processing and/or export. Indeed, a member of the THO complex that plays a role in mRNA export, THOC1, is co-precipitated with FMIP. The data we have acquired on FMIP suggest that it is a target for tyrosine kinase receptors that potentiate mRNA export.

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Section: Introductionmentioning

confidence: 99%

“…Its expression is up-regulated prominently in lymphoid organs. 12 Interestingly, GILZ expression is reported to be induced in the kidney, 13 in pluripotent mesenchymal cells, 14,15 and by GCs in erythroid progenitors, 16 thus suggesting GILZ plays a role not only in the immune system but also in several other physiologic systems.Within the immune system GILZ is strongly up-regulated by GC in the thymus, particularly, and in the bone marrow, spleen, and lymph nodes. 12 Expressed in resting B lymphocytes, it is downregulated when they are activated 17 ; in macrophages GC and interleukin 10 (IL-10) up-regulate it.…”

mentioning

confidence: 99%

Decrease of Bcl-xL and augmentation of thymocyte apoptosis in GILZ overexpressing transgenic mice

Delfino

Agostini

Spinicelli

et al. 2004

Blood

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Glucocorticoids promote thymocyte apoptosis and modulate transcription of numerous genes. GILZ (glucocorticoidinduced leucine zipper), being one of them, is strongly up-regulated in the thymus. To elucidate its function we generated transgenic mice overexpressing it specifically in the T-cell lineage and characterized its influence on thymus function. In young adult transgenic mice CD4 ؉ CD8 ؉ thymocyte number was significantly decreased and ex vivo thymocyte apoptosis was increased. Apoptotic pathway analysis detected reduced antiapoptotic B-cell leukemia XL (Bcl-xL) expression and increased activation of caspase-8 and caspase-3. Time-course experiments showed that in wild-type (WT) thymocytes GILZ up-regulation was followed by sequential Bcl-xL decreased expression and activation of caspase-8 and of caspase-3. Moreover, GILZ delivered inside WT thymocytes by a fusion protein with the transactivator of transcription (TAT) peptide decreased Bcl-xL and promoted their apoptosis. In aged mice perturbation of thymic subset numbers was amplified over time, as demonstrated by a further decrease in CD4 ؉ CD8 ؉ cells and increases in CD4 ؉ CD8 ؊ , CD4 ؊ CD8 ؊ , and CD8 ؉ CD4 ؊ cell counts. These results support the hypothesis that GILZ participates in the regulation of thymocyte apoptosis by glucocorticoids. IntroductionGlucocorticoids (GCs) are hormones and drugs that express their functions by binding and activating their specific intracellular receptor (GR), thus acting through genomic and nongenomic mechanisms. The thymus, one of their target organs, promotes thymocyte maturation to functional CD4 ϩ or CD8 ϩ single positive (SP) T lymphocytes that are ready to migrate to the periphery. T-cell development in the thymus is ordered by sequential steps that involve waves of cell proliferation and apoptosis. Apoptosis is a key process in thymus physiology and is triggered in 3 well-known ways: (1) negative selection, involving 5% of all thymocytes, eliminates autoreactive T-cell clones at the level of CD4 ϩ CD8 ϩ double-positive (DP) cells; (2) death by neglect involves 90% of DP thymocytes that are neither positively nor negatively selected; and (3) stress-induced cell death. 1 GCs promote apoptosis of DP thymocytes 2 but are not involved in apoptosis by negative selection. 3 Their role in apoptosis by neglect is uncertain, but they certainly mediate stress-induced apoptosis. 1 The apoptotic signaling pathway triggered by the synthetic GC dexamethasone (DEX) in thymocytes has recently been clarified to some extent. The GC receptor coordinates activation of gene transcription and caspase-8, -9, and -3 in a sequence that leads to thymocyte apoptosis. [4][5][6][7] Additionally, GC-mediated thymic apoptosis is regulated by many different molecules, and the B-cell leukemia 2 (Bcl-2) family of proteins is a critical regulator of apoptosis. 8 The family is subdivided into antiapoptotic members such as Bcl-2 and Bcl-xL, and proapoptotic members such as Bcl-2-associated X protein (Bax) and BCL-2 homologous antagonist/killer (Ba...

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A glucocorticoid‐induced leucine‐zipper protein, GILZ, inhibits adipogenesis of mesenchymal cells

Cited by 128 publications

References 25 publications

Prostaglandin F2α inhibits adipocyte differentiation via a Gαq‐Calcium‐Calcineurin‐Dependent signaling pathway

Prostaglandin F2α inhibits adipocyte differentiation via a Gαq‐Calcium‐Calcineurin‐Dependent signaling pathway

FMIP controls the adipocyte lineage commitment of C2C12 cells by downmodulation of C/EBPalpha

Decrease of Bcl-xL and augmentation of thymocyte apoptosis in GILZ overexpressing transgenic mice

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