Granulocyte-macrophage colony-stimulating factor and tetradecanoyl phorbol acetate induce a distinct, restricted subset of primary-response TIS genes in both proliferating and terminally differentiated myeloid cells.

Varnum, Brian; Lim, Robert W.; Kujubu, Dean A.; Luner, S J; Kaufman, Susan; Greenberger, Joel S.; Gasson, JC; Herschman, Harvey R.

doi:10.1128/mcb.9.8.3580

Cited by 68 publications

(25 citation statements)

References 29 publications

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“…The transcription of Zfp-36 is rapidly and dramatically stimulated by a variety of growth factors and mitogens, but not by agents acting solely through increases in cAMP levels (1,3,4). Several transcription factor-binding sites have been identified in the Zfp-36 promoter that are each partially responsible for activating transcription in response to serum or insulin (13).…”

Section: Tristetraprolin (Ttp)mentioning

confidence: 99%

See 1 more Smart Citation

Characteristics of the Intron Involvement in the Mitogen-induced Expression of Zfp-36

Lai

Thompson²,

Blackshear

1998

Journal of Biological Chemistry

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Zfp-36, the gene encoding the putative zinc finger protein tristetraprolin (TTP), is rapidly induced in fibroblasts by a variety of growth factors. Recent gene knockout experiments have shown that TTP-deficient mice developed arthritis, cachexia, and autoimmunity, all apparently mediated by an excess of tumor necrosis factor ␣. We recently showed that full serum inducibility of Zfp-36 requires elements in the promoter; in addition, removal of the single intron strikingly inhibited seruminduced TTP expression. We show here that replacement of the intron with unrelated sequences, or removal of 95% of the intron but retention of the splice sites, each resulted in the maintenance of approximately 45 and 19%, respectively, of full serum-induced expression. In addition, deletion of intron sequences base pairs 601-655 decreased the serum-induced expression of TTP by 65%. Sequence base pairs 618 -626 bound specifically to the transcription factor Sp1; mutation of this binding motif decreased TTP expression by 70%, suggesting that Sp1 binding to this motif contributes to serum induction of Zfp-36. We conclude that full serum-induced expression of Zfp-36 depends on the activation of conventional promoter elements as well as elements in the single intron, and that the presence per se of the intron in its natural location also contributes significantly to the regulated expression of this gene. Tristetraprolin (TTP)1 is a widely expressed protein containing two putative zinc fingers of the unusual CCCH class (1-5). It is the prototype of an enlarging group of proteins containing similar zinc fingers (6 -9). Although predominantly nuclear in quiescent fibroblasts, TTP is rapidly translocated from the nucleus to the cytoplasm by serum and other mitogens (10), an event that occurs concomitantly with stimulated serine phosphorylation (11). Although TTP has no proven function, disruption of its gene, Zfp-36, in mice leads to a complex syndrome that includes erosive arthritis, conjunctivitis, myeloid hyperplasia, cachexia, and autoimmunity (12). All aspects of the syndrome were prevented by pretreating the animals with monoclonal antibodies to tumor necrosis factor ␣ (TNF␣) (12). These data suggest that a potential function of TTP is to regulate the production of TNF␣ by certain cell types. They also indicate the possibility that defects in Zfp-36 might be involved in the pathogenesis of certain human conditions in which TNF␣ excess plays a role, such as rheumatoid arthritis and systemic lupus erythematosus.The transcription of Zfp-36 is rapidly and dramatically stimulated by a variety of growth factors and mitogens, but not by agents acting solely through increases in cAMP levels (1, 3, 4). Several transcription factor-binding sites have been identified in the Zfp-36 promoter that are each partially responsible for activating transcription in response to serum or insulin (13). In addition, we showed that the single intron of Zfp-36 also participates in the regulation of its transcription, since deletion of the intron results in a...

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Section: Tristetraprolin (Ttp)mentioning

confidence: 99%

“…1 is a widely expressed protein containing two putative zinc fingers of the unusual CCCH class (1)(2)(3)(4)(5). It is the prototype of an enlarging group of proteins containing similar zinc fingers (6 -9).…”

Section: Tristetraprolin (Ttp)mentioning

confidence: 99%

Characteristics of the Intron Involvement in the Mitogen-induced Expression of Zfp-36

Lai

Thompson²,

Blackshear

1998

Journal of Biological Chemistry

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“…TTP, the best-studied TTP/ZFP36 family member, is the product of the Zfp36 in mouse and ZFP36 in humans [27][28][29]. TTP cDNA clones were initially isolated by three laboratories based on its rapid and dramatic transcriptional induction in fibroblasts in response to insulin, phorbol esters and serum [27,28,30].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation site analysis of the anti-inflammatory and mRNA-destabilizing protein tristetraprolin

Cao¹,

Deterding²,

Blackshear³

2007

Expert Review of Proteomics

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Tristetraprolin (TTP) is a member of the CCCH zinc finger proteins and is an anti-inflammatory protein. Mice deficient in TTP develop a profound inflammatory syndrome with erosive arthritis, autoimmunity and myeloid hyperplasia. TTP binds to mRNA AU-rich elements with high affinity for UUAUUUAUU nucleotides and causes destabilization of those mRNA molecules. TTP is phosphorylated extensively in vivo and is a substrate for multiple protein kinases in vitro. A number of approaches have been used to identify its phosphorylation sites. This article highlights the recent progress and different approaches utilized for the identification of phosphorylation sites in mammalian TTP. Important but limited results are obtained using traditional methods including in vivo labeling, site-directed mutagenesis, phosphopeptide mapping and protein sequencing. Mass spectrometry including MALDI/MS, MALDI/MS/MS, LC/MS/MS, IMAC/MALDI/MS/MS and multidimensional protein identification technology (MudPIT) has led the way in identifying TTP phosphorylation sites. The combination of these approaches has identified multiple phosphorylation sites in mammalian TTP, some of which are predicted by motif scanning to be phosphorylated by several protein kinases. This information should provide the molecular basis for future investigation of TTP's regulatory functions in controlling pro-inflammatory cytokines.

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“…In addition, NGFI-A is induced in response to agents which trigger differentiation pathways. NGFI-A expression is activated in nerve growth factor (NGF)-stimulated differentiation of PC12 cells (5,6,24), during differentiation of preosteoblastic cells (43), and also during B-cell maturation (39,40,48). NGFI-A has been implicated in macrophage differentiation (17) and regulation of growth arrest and apoptotic pathways in melanoma cell lines (26,38) and has been shown to be required for regulation of pituitary gonadotropin production (19).…”

mentioning

confidence: 99%

NAB2, a Corepressor of NGFI-A (Egr-1) and Krox20, Is Induced by Proliferative and Differentiative Stimuli

Svaren

Sevetson

Apel

et al. 1996

Molecular and Cellular Biology

331

328

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Previous work had identified a corepressor, NAB1, which represses transcriptional activation mediated by NGFI-A (also known as Egr-1, zif268, and Krox24) and Krox20. These zinc finger transcription factors are encoded by immediate-early genes and have been implicated in a wide variety of proliferative and differentiative processes. We have isolated and characterized another corepressor, NAB2, which is highly related to NAB1 within two discrete domains. The first conserved domain of NAB2 mediates an interaction with the R1 domain of NGFI-A. NAB2 represses the activity of both NGFI-A and Krox20, and its expression is regulated by some of the same stimuli that induce NGFI-A expression, including serum stimulation of fibroblasts and nerve growth factor stimulation of PC12 cells. The human NAB2 gene has been localized to chromosome 12q13.3-14.1, a region that is rearranged in several solid tumors, lipomas, uterine leiomyomata, and liposarcomas. Sequencing of the Caenorhabditis elegans genome has identified a gene that bears high homology to both NAB1 and NAB2, suggesting that NAB molecules fulfill an evolutionarily conserved role.Transcriptional control plays a vital role in regulating fundamental cellular processes such as proliferation, differentiation, and cell death. Changes in gene expression are often effected by altering the expression level, activity, and/or nuclear localization of transcription factors that bind to promoter and enhancer regions. In addition, many transcription factors are regulated by direct interactions with other proteins which modulate the level of transcriptional activation.

show abstract

Granulocyte-macrophage colony-stimulating factor and tetradecanoyl phorbol acetate induce a distinct, restricted subset of primary-response TIS genes in both proliferating and terminally differentiated myeloid cells.

Cited by 68 publications

References 29 publications

Characteristics of the Intron Involvement in the Mitogen-induced Expression of Zfp-36

Characteristics of the Intron Involvement in the Mitogen-induced Expression of Zfp-36

Phosphorylation site analysis of the anti-inflammatory and mRNA-destabilizing protein tristetraprolin

NAB2, a Corepressor of NGFI-A (Egr-1) and Krox20, Is Induced by Proliferative and Differentiative Stimuli

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