Transcriptional regulation by the γ5 subunit of a heterotrimeric G protein during adipogenesis

Park, Jin Gyoon; Muise, Aleixo M.; Gong, He; Kim, Sung Woo; Ro, Hyo‐Sung

doi:10.1093/emboj/18.14.4004

Cited by 58 publications

(54 citation statements)

References 46 publications

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“…Levels of Gg 5 protein were shown to decrease during the ®rst 2 days of in vitro di erentiation of 3T3-L1 cells into adipocytes. Moreover, a Gbg 5 -dimer was found to be associated with AEBP1 in the nucleus of 3T3-L1 cells and to attenuate its transcriptional repression activity (Park et al, 1999). As detailed above, Gg 5 may be uniquely suited to translocate to the nucleus because of its distinct posttranslational modi®cations (Cook et al, 1998).…”

Section: Additional Roles Of Gbg-dimers In Proliferation and DI Erentmentioning

confidence: 90%

Heterotrimeric G-protein βγ-dimers in growth and differentiation

Schwindinger¹,

Robishaw²

2001

Oncogene

184

155

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Section: Additional Roles Of Gbg-dimers In Proliferation and DI Erentmentioning

confidence: 90%

Heterotrimeric G-protein βγ-dimers in growth and differentiation

Schwindinger¹,

Robishaw²

2001

Oncogene

184

155

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“…G␣ proteins. We are unaware of evidence for nuclear localization of G␣ subunits, although Park et al (31) recently showed that G␤␥ 5 complexes localize to the nucleus in NIH 3T3-L1 cells and attenuate the transcriptional repression activity of adipocyte enhancer-binding protein (AEBP1). If G␣ subunits do not localize to and exert regulatory effects in the nucleus, it seems possible that RGS proteins could have other functions in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Novel Alternative Splicing and Nuclear Localization of HumanRGS12 Gene Products

Chatterjee

Fisher

2000

Journal of Biological Chemistry

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RGS proteins are GTPase-activating proteins for certain G␣ subunits, accelerating the shutoff mechanism of G protein signaling, and also may interact with receptors and effectors to modulate G protein signaling. Here, we report identification of 12 distinct transcripts of human RGS12 that arise by unusually complex splicing of the RGS12 gene, which spans 70 kilobase pairs of genomic DNA and contains 16 exons. These transcripts arise by both cis-and trans-splicing mechanisms, are expressed in a tissue-specific manner, and encode proteins ranging in size from 356 to 1447 amino acids. Both 5-and 3-splicing of two primary RGS12 transcripts occur to generate RGS12 mRNAs encoding proteins with four distinct N-terminal domains, three distinct C-terminal domains, and a common internal region where the semiconserved RGS domain is located. Confocal microscopy and subcellular fractionation of COS-7 cells expressing RGS12 proteins with three different N termini (brain (B), peripheral (P), and trans-spliced (TS)) and a shared short (S) C-terminal domain demonstrated exclusive nuclear localization of these proteins and an influence of the N-terminal region on the pattern of intranuclear distribution. Both native RGS12TS-S in HEK-293T cells and ectopically expressed RGS12TS-S localized to discrete nuclear foci (dots), a characteristic of various tumor suppressor proteins. Subnuclear localization of RGS12TS-S into nuclear dots was cell cycle-dependent. Native RGS12TS-S associated with the metaphase chromosome during mitosis, and ectopically expressed RGS12TS-S induced formation of abnormally shaped and multiple nuclei in COS-7 cells. Expression of RGS12 proteins with long and intermediate C-terminal domains was not observed in COS-7 cells, suggesting that 3-splicing of RGS12 transcripts may influence the expression or stability of the encoded proteins. These results document extraordinary structural complexity in the RGS12 family and the role of alternative splicing and cell cycle-dependent mechanisms in expression and subnuclear targeting of RGS12 proteins.Heterotrimeric G proteins are components of many major signaling systems used by cells to transduce a variety of signals (neurotransmitters, hormones, light, and olfactory and taste signals) from specific cell-surface receptors to effector proteins (see Refs. 1 and 2 for review). These receptors activate G proteins by stimulating exchange of GTP for GDP on the ␣ subunit (G␣) of the inactive G protein heterotrimer (G␣␤␥) to promote dissociation into G␣-GTP and G␤␥ subunits. Both of these G protein subunits function as signal-transducing molecules by regulating activities of various effector proteins including enzymes and ion channels. The intensity and duration of signaling by G proteins are highly regulated. The key element that controls the lifetime of active G␣ and G␤␥ is the intrinsic GTPase activity of the G␣ subunits, producing G␣-GDP and its reassembly with G␤␥.RGS (regulators of G protein signaling) proteins constitute a family of proteins originally defined by the pr...

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“…AEBP1 is involved in several biological processes including adipogenesis, macrophage cholesterol homeostasis, and inflammation (Park et al, 1999;Kim et al, 2001;Zhang et al, 2005;Majdalawieh et al, 2006). In macrophages, AEBP1 was shown to promote the expression of IL-6, TNF-␣, MCP-1, and iNOS (Majdalawieh et al, 2006), This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06 -03-0217) on January 3, 2007. whose expression is tightly regulated by NF-B activity (Tak and Firestein, 2001;Yamamoto and Gaynor, 2001).…”

Section: Introductionmentioning

confidence: 99%

Adipocyte Enhancer-binding Protein-1 Promotes Macrophage Inflammatory Responsiveness by Up-Regulating NF-κB via IκBα Negative Regulation

Majdalawieh

Zhang

2007

MBoC

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Nuclear factor B (NF-B) subunits comprise a family of eukaryotic transcription factors that are critically involved in cell proliferation, inflammation, and apoptosis. Under basal conditions, NF-B subunits are kept under inhibitory regulation by physical interaction with NF-B inhibitors (IB subunits) in the cytosol. Upon stimulation, IB subunits become phosphorylated, ubiquitinated, and subsequently degraded, allowing NF-B subunits to translocate to the nucleus and bind as dimers to B responsive elements of target genes. Previously, we have shown that AEBP1 enhances macrophage inflammatory responsiveness by inducing the expression of various proinflammatory mediators. Herein, we provide evidence suggesting that AEBP1 manifests its proinflammatory function by up-regulating NF-B activity via hampering IB␣, but not IB␤, inhibitory function through protein-protein interaction mediated by the discoidin-like domain (DLD) of AEBP1. Such interaction renders IB␣ susceptible to enhanced phosphorylation and degradation, subsequently leading to augmented NF-B activity. Collectively, we propose a novel molecular mechanism whereby NF-B activity is modulated by means of protein-protein interaction involving AEBP1 and IB␣. Moreover, our study provides a plausible mechanism explaining the differential regulatory functions exhibited by IB␣ and IB␤ in various cell types. We speculate that AEBP1 may serve as a potential therapeutic target for the treatment of various chronic inflammatory diseases and cancer.

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Transcriptional regulation by the γ5 subunit of a heterotrimeric G protein during adipogenesis

Cited by 58 publications

References 46 publications

Heterotrimeric G-protein βγ-dimers in growth and differentiation

Heterotrimeric G-protein βγ-dimers in growth and differentiation

Novel Alternative Splicing and Nuclear Localization of HumanRGS12 Gene Products

Adipocyte Enhancer-binding Protein-1 Promotes Macrophage Inflammatory Responsiveness by Up-Regulating NF-κB via IκBα Negative Regulation

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