Transcriptional repression by nuclear receptors: mechanisms and role in disease

Love, Jamie; Gooch, JT; Nagy, L; Chatterjee, Vkk; Schwabe, John W. R.

doi:10.1042/0300-5127:0280390

Cited by 11 publications

(7 citation statements)

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“…We have shown previously that dominant-negative inhibition by PPARγ mutants (P467L, V290M), is mediated by repression of target genes by DNA-bound mutant receptors, analogous to mechanisms of other mutant nuclear receptors (e.g., the v-erbA oncogene, TRβ mutants in Resistance to Thyroid Hormone, PZLF-RARα fusion proteins in promyelocytic leukaemia) (Love et al., 2000). In contrast, the missense DBD and LBD truncation mutants identified here are unable to bind DNA, yet can inhibit WT PPARγ action, suggesting a different mechanism of transcriptional interference.…”

Section: Resultsmentioning

confidence: 99%

Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance

et al. 2006

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SummaryPPARγ is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARγ in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARγ coactivators and inhibit coexpressed wild-type receptor. Expression of PPARγ target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARγ action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.

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Section: Resultsmentioning

confidence: 99%

Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance

et al. 2006

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“…(b) Upon ligand (L) activation, the CoRep dissociates from the heterodimer, that now recruits co-activators (CoAct) and increases transcription of target genes, such as ILK and PDK1 [24]. (c) The CoRep that is released from the heterodimer can also transrepress non-PPRE-harbouring genes [46,47]. De novo protein synthesis is not required for these modes of action.…”

Section: Wound Re-epithelializationmentioning

confidence: 99%

Critical roles of the nuclear receptor PPARβ (peroxisome-proliferator-activated receptor β) in skin wound healing

Tan

Michalik

Di‐Poï

et al. 2004

Biochemical Society Transactions

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The PPARs (peroxisome-proliferator-activated receptors) alpha, beta/delta and gamma belong to the nuclear hormone receptor superfamily. While all three receptors are undetectable in adult mouse interfollicular epidermis, PPARbeta expression and activity is strongly re-activated by inflammatory stimuli during epidermal injury. The pro-inflammatory cytokine TNFalpha (tumour necrosis factor alpha) stimulates transcription of the PPARbeta gene via an activator protein-1 site in its promoter and it also triggers the production of PPARbeta ligands in keratinocytes. This increase of PPARbeta activity in these cells up-regulates the expression of integrin-linked kinase and 3-phosphoinositide-dependent kinase-1, which phosphorylates protein kinase B-alpha (Akt1). The resulting increase in Akt1 activity suppresses apoptosis and ensures the presence of a sufficient number of viable keratinocytes at the wound margin for re-epithelialization. Together, these observations reveal that PPARbeta takes on multiple roles and contributes favourably to the process of wound closure.

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“…Other common dominant negative mutations include truncated molecules that maintain ligand-or target-binding functions but lack other functional domains (23)(24)(25)(26). Dominant negative mutations work by inhibiting the function of the wild-type allele, which often occurs by the mutated allele "poisoning" a molecular complex or titrating key components required for function.…”

Section: Downloaded Frommentioning

confidence: 99%

Truncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1 by 9-cis-retinoic acid and 22-R-hydroxycholesterol

Wellington

Yang

Zhou

et al. 2002

Journal of Lipid Research

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Mutations in ABCA1 uniformly decrease plasma HDL-cholesterol (HDL-C) and reduce cholesterol efflux, yet different mutations in ABCA1 result in different phenotypic effects in heterozygotes. For example, truncation mutations result in significantly lower HDL-C and apoliprotein A-I (apoA-I) levels in heterozygotes compared with nontruncation mutations, suggesting that truncation mutations may negatively affect the wild-type allele. To specifically test this hypothesis, we examined ABCA1 protein expression in response to 9-cis -retinoic acid (9-cis -RA) and 22-R -hydroxycholesterol (22-R -OH-Chol) in a collection of human fibroblasts representing eight different mutations and observed that truncation mutations blunted the response to oxysterol stimulation and dominantly suppressed induction of the remaining full-length allele to 5-10% of wild-type levels. mRNA levels between truncation and nontruncation mutations were comparable, suggesting that ABCA1 expression was suppressed at the protein level. Dominant negative activity of truncated ABCA1 was recapitulated in an in vitro model using transfected Cos-7 cells. Our results suggest that the severe reduction of HDL-C in patients with truncation mutations may be at least partly explained by dominant negative suppression of expression and activity of the remaining full-length ABCA1 allele. These data suggest that ABCA1 requires a physical association with itself or other molecules for normal function and has important pharmacogenetic implications for individuals with truncation mutations.

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Transcriptional repression by nuclear receptors: mechanisms and role in disease

Cited by 11 publications

References 0 publications

Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance

Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance

Critical roles of the nuclear receptor PPARβ (peroxisome-proliferator-activated receptor β) in skin wound healing

Truncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1 by 9-cis-retinoic acid and 22-R-hydroxycholesterol

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