The regulation of GM-CSF is dependent on a complex interplay of multiple nuclear proteins

Kaushansky, Kenneth; O'Rork, Colleen; Shoemaker, Sara G.; McCarty, John M.

doi:10.1016/0161-5890(95)00156-5

Cited by 19 publications

(23 citation statements)

References 32 publications

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“…Examples of cellular gene products that associate with Oct-1 and potentiate its transcriptional activity include Pit-1/GHF-1 (10) and Jun family proteins (51), which contribute to the induction of the rat PRL and the interleukin-2 gene, respectively. Furthermore, transcriptional enhancement of interleukin-3 and granulocyte-macrophage colony-stimulating factor genes by Oct-1 are potentiated by its association with 43-and 45-kDa proteins (52). As in the case for the above genes, we have identified a second protein, Pbx, which binds to the PRL3 nGRE and contributed together with Oct-1 to the regulation of the expression (Fig.…”

Section: Figmentioning

confidence: 88%

Glucocorticoids Repress Transcription from a Negative Glucocorticoid Response Element Recognized by Two Homeodomain-containing Proteins, Pbx and Oct-1

Subramaniam

Cairns

Okret

1998

Journal of Biological Chemistry

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Section: Figmentioning

confidence: 88%

Glucocorticoids Repress Transcription from a Negative Glucocorticoid Response Element Recognized by Two Homeodomain-containing Proteins, Pbx and Oct-1

Subramaniam

Cairns

Okret

1998

Journal of Biological Chemistry

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“…These findings have implications for the generation of T cell memory responses and, by extension, the ability to resist infection by certain pathogens. Oct1 is associated with the expression of multiple cytokines, including Il-3, Il-5, Il-8, Il-12/23 (55)(56)(57)(58)(59)(60), and more recently Il-4 and Il-13 (61,62). Oct1 is also associated with other loci of immunological interest (e.g.…”

Section: Discussionmentioning

confidence: 99%

Oct1 Is a Switchable, Bipotential Stabilizer of Repressed and Inducible Transcriptional States

Shakya

Kang

Chumley

et al. 2011

Journal of Biological Chemistry

127

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Little is known regarding how the Oct1 transcription factor regulates target gene expression. Using murine fibroblasts and two target genes, Polr2a and Ahcy, we show that Oct1 recruits the Jmjd1a/KDM3A lysine demethylase to catalyze the removal of the inhibitory histone H3K9 dimethyl mark and block repression. Using purified murine T cells and the Il2 target locus, and a colon cancer cell line and the Cdx2 target locus, we show that Oct1 recruits the NuRD chromatin-remodeling complex to promote a repressed state, but in a regulated manner can switch to a different capacity and mediate Jmjd1a recruitment to block repression. These findings indicate that Oct1 maintains repression through a mechanism involving NuRD and maintains poised gene expression states through an antirepression mechanism involving Jmjd1a. We propose that, rather than acting as a primary trigger of gene activation or repression, Oct1 is a switchable stabilizer of repressed and inducible states.The POU 2 (Pit-1, Oct1/2, Unc-86) transcription factor family includes ϳ13 mammalian paralogs as well as representatives from other metazoans (1). The best known example, Oct4/POU5F1, regulates embryonic stem (ES) cell identity and is a key factor used to generate induced pluripotent stem cells from somatic cells (2-5). Oct1/POU2F1 is related to Oct4 and possesses similar in vitro DNA binding specificity (for reviewed, see Ref. 6). As with many transcription factors, these proteins are known to regulate gene expression both positively and negatively (e.g. 7, 8); however, their activity has been thought to be determined by gene context and not subject to regulation.Loss of Oct1 inhibits oncogenic transformation in mouse embryonic fibroblasts (MEFs) and tumorigenicity in p53-deficient mice and xenograft assays, while having little effect on cell growth in culture or transformation by serial passage (9). One study indicates that Oct1 levels are increased in some human gastric cancers (10). In contrast, multiple studies have identified coordinate up-regulation of Oct1 target genes in lung and breast adenocarcinomas, leukemias, and myeloid leukemia stem cells, without concurrent up-regulation of Oct1 itself (11)(12)(13)(14), suggesting that Oct1 activity may be deregulated in malignancy. Recent findings showing post-translational regulation of Oct1 support this possibility (15). Although Oct1 has been studied intensively, our current understanding of how it regulates gene transcription is surprisingly limited (see for example, Ref. 16).Here, we show using three different systems (fibroblasts, primary T cells, and a colon cancer cell line) that Oct1 is a bipotential and switchable transcriptional regulator. In fibroblasts, Oct1 mediates recruitment of the Jmjd1a histone demethylase to target genes (Polr2a and Ahcy) following oxidative stress exposure. In the absence of Oct1, Jmjd1a fails to be recruited, H3K9me2 levels are elevated, and inappropriate repression is observed. In contrast, Oct1 recruits the nucleosome remodeling and histone deacetylation (NuRD/Mi...

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“…First, it changes the NF-B-type complexes that bind to the B site, and second, it reduces the binding of Sp1 to an overlapping site. It has previously been shown that mutation of the Sp1 region influences binding to the B site, and it is likely that these elements operate as a functional unit (29,43). It has also been shown that NF-B and Sp1 cooperatively activate the HIV long terminal repeat (51), and that at least part of this effect is due to the requirement of both proteins for correct nucleosome positioning on the HIV long terminal repeat (52,53).…”

Section: Discussionmentioning

confidence: 99%

“…This element cannot, however, function alone, but requires the adjacent NF-B and Sp1 sites (26 -28). The proximal NF-B site binds a classical RelA/p50 complex following activation and is responsive to TCR signals (26,27,29). The entire CD28RR appears to act as a unit and may form an enhanceosome-type structure in response to T cell activation.…”

mentioning

confidence: 99%

A NF-κB/Sp1 Region Is Essential for Chromatin Remodeling and Correct Transcription of a Human Granulocyte- Macrophage Colony-Stimulating Factor Transgene

Cakouros

Cockerill

Bert

et al. 2001

The Journal of Immunology

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The GM-CSF gene is expressed following activation of T cells. The proximal promoter and an upstream enhancer have previously been characterized using transfection and reporter assays in T cell lines in culture. A 10.5-kb transgene containing the entire human GM-CSF gene has also been shown to display inducible, position-independent, copy number-dependent transcription in mouse splenocytes. To determine the role of individual promoter elements in transgene function, mutations were introduced into the proximal promoter and activity assessed following the generation of transgenic mice. Of four mutations introduced into the transgene promoter, only one, in an NF-κB/Sp1 region, led to decreased induction of the transgene in splenocytes or bone marrow-derived macrophages. This mutation also affected the activity of reporter gene constructs stably transfected into T cell lines in culture, but not when transiently transfected into the same cell lines. The mutation alters the NF-κB family members that bind to the NF-κB site as well as reducing the binding of Sp1 to an adjacent element. A DNase I hypersensitive site that is normally generated at the promoter following T cell activation on the wild-type transgene does not appear in the mutant transgene. These results suggest that the NF-κB/Sp1 region plays a critical role in chromatin remodeling and transcription on the GM-CSF promoter in primary T cells.

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The regulation of GM-CSF is dependent on a complex interplay of multiple nuclear proteins

Cited by 19 publications

References 32 publications

Glucocorticoids Repress Transcription from a Negative Glucocorticoid Response Element Recognized by Two Homeodomain-containing Proteins, Pbx and Oct-1

Glucocorticoids Repress Transcription from a Negative Glucocorticoid Response Element Recognized by Two Homeodomain-containing Proteins, Pbx and Oct-1

Oct1 Is a Switchable, Bipotential Stabilizer of Repressed and Inducible Transcriptional States

A NF-κB/Sp1 Region Is Essential for Chromatin Remodeling and Correct Transcription of a Human Granulocyte- Macrophage Colony-Stimulating Factor Transgene

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