Factors controlling the expression of mouse mammary tumour virus

Günzburg, Walter H.; Salmons, Brian

doi:10.1042/bj2830625

Cited by 74 publications

(40 citation statements)

References 134 publications

(106 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Luciferase reporter vectors were tested that contain enhancer/promoter regions from the androgen-regulated genes, PSA (16,17), probasin (18), sex-limited protein (pGC⌬9) (19,20), and MMTV (21)(22)(23). The role of the WXXLF and FXXLF motifs and effects of TIF2 coactivation on luciferase activity were determined using wild-type AR (AR-FXXLF/ WXXLF) or AR in which FXXLF was changed to FXXAA, WXXLF was changed to AXXAA, or both mutations were created in the same protein.…”

Section: Resultsmentioning

confidence: 99%

“…In our studies, the MMTV, PSA, and probasin luciferase reporters were activated by AR and GR, whereas there was little GR transactivation of pGL⌬9. It is well established that GR stimulates the MMTV promoter (21)(22)(23), whereas the probasin (34,35) and pGL⌬9 (20) enhancer/promoters are reported to be selectively activated by AR. It was the PSA, probasin and pGL⌬9 enhancer/promoters that showed increased transactivation by the GR chimera with an imposed N/C interaction.…”

Section: Tif2 Coactivation Of Ar-mediated Transactivation Of the Psa mentioning

confidence: 99%

See 1 more Smart Citation

Dependence of Selective Gene Activation on the Androgen Receptor NH2- and COOH-terminal Interaction

Lee

Minges

et al. 2002

Journal of Biological Chemistry

146

143

View full text Add to dashboard Cite

The agonist-induced androgen receptor NH 2 -and COOH-terminal (N/C) interaction is mediated by the FXXLF and WXXLF NH 2 -terminal motifs. Here we demonstrate that agonist-dependent transactivation of prostate-specific antigen (PSA) and probasin enhancer/promoter regions requires the N/C interaction, whereas the sex-limited protein gene and mouse mammary tumor virus long terminal repeat do not. Transactivation of PSA and probasin response regions also depends on activation function 1 (AF1) in the NH 2 -terminal region but can be increased by binding an overexpressed p160 coactivator to activation function 2 (AF2) in the ligand binding domain. The dependence of the PSA and probasin enhancer/promoters on the N/C interaction for transactivation allowed us to demonstrate that in the presence of androgen, the WXXLF motif with the sequence 433 WHTLF 437 contributes as an inhibitor to AR transactivation. We further show that like the FXXLF and LXXLL motifs, the WXXLF motif interacts in the presence of androgen with AF2 in the ligand binding domain. Sequence comparisons among species indicate greater conservation of the FXXLF motif compared with the WXXLF motif, paralleling the functional significance of these binding motifs. The data provide evidence for promoter-specific differences in the requirement for the androgen receptor N/C interaction and in the contributions of AF1 and AF2 in androgen-induced gene regulation.Steroid receptors are ligand-activated transcription factors that regulate gene activation through a series of events triggered by high affinity hormone binding and mediated by receptor binding to response element DNA and coactivators. At least two domains have been identified that mediate nuclear receptor interactions with coregulators. These are activation function 1 (AF1) 1 in the NH 2 -terminal region and activation function 2 (AF2) in the ligand binding domain. The AF2 binding surface in the ligand binding domain is comprised of helices 3, 4, and 12 and forms after hormone binding. For many nuclear receptors, transactivation depends on AF2 recruitment of p160 coactivator complexes that have histone acetyl transferase activity to modify chromatin structure (1). The p160 coactivators are a group of proteins that include steroid receptor coactivator 1 (SRC1), transcriptional intermediary protein 2 (TIF2, GRIP1 or SRC2), and the steroid receptor coactivator 3 subfamily (SRC3). Interaction with AF2 is mediated by the p160 coactivator LXXLL motif that forms an amphipathic ␣-helix and binds the AF2 hydrophobic binding surface in the nuclear receptor ligand binding domain (2-5). For the androgen receptor (AR), the functional importance of AF2 recruitment of p160 coactivators is unclear, with data implicating the AR NH 2 -terminal AF1 region in AR-mediated gene activation. The AF2 binding site in the AR ligand binding domain was shown to mediate the agonist-induced NH 2 -and COOH-terminal (N/C) interaction (6 -10). Agonist-induced N/C interdomain interactions are also reported for the estrogen (11) and progest...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Tif2 Coactivation Of Ar-mediated Transactivation Of the Psa mentioning

confidence: 99%

Dependence of Selective Gene Activation on the Androgen Receptor NH2- and COOH-terminal Interaction

Lee

Minges

et al. 2002

Journal of Biological Chemistry

146

143

View full text Add to dashboard Cite

show abstract

“…The hormonally responsive MMTV promoter is induced during late pregnancy and lactation (reviewed in Gunzburg and Salmons, 1992). Thus, accelerated tumor development in bitransgenic mice could simply be due to increased expression of the transgene in these animals.…”

Section: Accelerated and Synchronous Tumorigenesis In Bitransgenic MImentioning

confidence: 99%

Sustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors

et al. 2006

View full text Add to dashboard Cite

Epidemiological studies indicate that parity enhances HER2/ErbB2/Neu-induced breast tumorigenesis. Furthermore, recent studies using multiparous, ErbB2/Neu-overexpressing mouse mammary tumor virus (MMTV-Neu) mice have shown that parity induces a population of cells that are targeted for ErbB2/Neu-induced transformation. Although parity accelerates mammary tumorigenesis, the pattern of tumor development in multiparous MMTV-Neu mice remains stochastic, suggesting that additional events are required for ErbB2/Neu to cause mammary tumors. Whether such events are genetic in nature or reflective of the dynamic hormonal control of the gland that occurs with pregnancy remains unclear. We postulated that young age at pregnancy initiation or chronic trophic maintenance of mammary epithelial cells might provide a cellular environment that significantly increases susceptibility to ErbB2/Neu-induced tumorigenesis. MMTV-Neu mice that were maintained pregnant or lactating beginning at 3 weeks of age demonstrated accelerated tumorigenesis, but this process was still stochastic, indicating that early pregnancy does not provide the requisite events of tumorigenesis. However, bitransgenic mice that were generated by breeding MMTV-Neu mice with a luteinizing hormone-overexpressing mouse model of ovarian hyperstimulation developed multifocal mammary tumors in an accelerated, synchronous manner compared to virgin MMTV-Neu animals. This synchrony of tumor development in the bitransgenic mice suggests that trophic maintenance of the mammary gland provides the additional events required for tumor formation and maintains the population of cells that are targeted by ErbB2/Neu for transformation. Both the synchrony of tumor appearance and the ability to characterize a window of commitment by ovariectomy/palpation studies permitted microarray analysis to evaluate changes in gene expression over a defined timeline that spans the progression from normal to preneoplastic mammary tissue. These approaches led to identification of several candidate genes whose expression changes in the mammary gland with commitment to ErbB2/Neu-induced tumorigenesis, suggesting that they may either be regulated by ErbB2/Neu and/or contribute to tumor formation.

show abstract

“…DNA elements mediating positive (40,57,69,70,110) or negative (40,45,57,70,73) regulation have been identified by functional assays in tissue culture cells, and elements involved in tissue-specific expression have been defined by analyses of naturally occurring variant LTRs in pathologic situations (5, 29,47,56,66,67,105) or by the generation of transgenic mice (72,90; reviewed in reference 44). An important class of positively acting factors comprises several types of steroid hormone-receptor complexes: glucocorticoids (13), progestins (18), and androgens (28).…”

mentioning

confidence: 99%

Stably integrated mouse mammary tumor virus long terminal repeat DNA requires the octamer motifs for basal promoter activity.

Buetti¹

1994

Mol. Cell. Biol.

View full text Add to dashboard Cite

In the mouse mammary tumor virus promoter, a tandem of octamer motifs, recognized by ubiquitous and tissue-restricted Oct transcription factors, is located upstream of the TATA box and next to a binding site for the transcription factor nuclear factor I (NF-I). Their function was investigated with mutant long terminal repeats under different transfection conditions in mouse Ltk-cells and quantitative Si nuclease mapping of the transcripts. In stable transfectants, which are most representative of the state of proviral DNA with respect to both number of integrated DNA templates and chromatin organization, a long terminal repeat mutant of both octamer sites showed an average 50-fold reduction of the basal transcription level, while the dexamethasonestimulated level was unaffected. DNase I in vitro footprinting assays with L-cell nuclear protein extracts showed that the mutant DNA was unable to bind octamer factors but had a normal footprint in the NF-I site. I conclude that mouse mammary tumor virus employs the tandem octamer motifs of the viral promoter, recognized by the ubiquitous transcription factor Oct-i, for its basal transcriptional activity and the NF-I binding site, as previously shown, for glucocorticoid-stimulated transcription. A deletion mutant with only one octamer site showed a marked base-level reduction at high copy number but little reduction at low copies of integrated plasmids. The observed transcription levels may depend both on the relative ratio of transcription factors to DNA templates and on the relative affinity of binding sites, as determined by oligonucleotide competition footprinting. (14,15,21,48,52,61, 82) and progestins (17,20,41). Analysis by linker-scanning (LS) mutagenesis has defined multiple, distinct sequence elements acting cooperatively to achieve maximal glucocorticoid stimulation of the MMTV promoter (15, 16, 52). Two of them are located in DNA segments shown to bind in vitro the purified glucocorticoid receptor: the strongest, distal element (around position -175) cooperates with a weaker proximal one, which in turn requires a nuclear factor I (NF-I) binding site centered around position -70 (2,12,15,16,19,68,106). In vivo, NF-I binding was observed in conjunction with alterations of the chromatin structure brought about by hormone treatment (3,27, 81).In vitro footprinting studies with nuclear protein extracts of mouse tissues showed a protection against DNase I * Phone: (41 21) (-62 to -37) next to the NF-I binding site that are related to the octamer/NF-III recognition motifs and present as a 10-bp direct repeat (65). A similar configuration of adjacent NF-I and NF-III sites is found in the DNA of adenovirus type 2, in which both sites are required for viral DNA replication (84-86). Octamerrelated sequences occur in transcriptional regulatory elements of several genes, including the promoters of histone H2B (100) and of immunoglobulin light-and heavy-chain genes (30,79) and the enhancers of immunoglobulin heavy chain (6, 37), Ul and U2 small nuclear RNAs (25,51,6...

show abstract

Factors controlling the expression of mouse mammary tumour virus

Cited by 74 publications

References 134 publications

Dependence of Selective Gene Activation on the Androgen Receptor NH2- and COOH-terminal Interaction

Dependence of Selective Gene Activation on the Androgen Receptor NH2- and COOH-terminal Interaction

Sustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors

Stably integrated mouse mammary tumor virus long terminal repeat DNA requires the octamer motifs for basal promoter activity.

Contact Info

Product

Resources

About