Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In MCF7 human breast cancer cells, cathepsin-D and pS2 mRNAs are specifically and directly induced by estrogens at the transcriptional level. We studied the regulation of expression of these two genes by growth factors that are also mitogenic in this cell line. We show that pS2 mRNA, like cathepsin-D mRNA, is rapidly induced 2- to 4-fold by epidermal growth factor. The effect of epidermal growth factor on these two mRNAs was dependent upon de novo protein synthesis, indicating a different mechanism of regulation than with estradiol. Other peptide growth factors, such as insulin, insulin-like growth factor I, and basic fibroblast growth factor, also increased up to 3-fold the steady state levels of the two mRNAs in MCF7 cells. The pS2 mRNA, but not cathepsin-D mRNA, was also induced up to 8-fold by protein kinase-C activation with 12-O-tetradecanoylphorbol-13-acetate, suggesting the possible involvement of this transduction pathway in pS2 mRNA induction. The effect of 12-O-tetradecanoylphorbol-13-acetate was time and dose dependent and required protein synthesis. In addition, treatment by agents elevating cAMP increased pS2 mRNA accumulation 4-fold, whereas it had no effect on cathepsin-D mRNA levels. These results demonstrate that cathepsin-D and pS2 genes are under complex regulation in MCF7 cells, since growth factors stimulate their expression via indirect mechanisms contrasting with the primary transcriptional effects of estrogens.
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PMID:Regulation of cathepsin-D and pS2 gene expression by growth factors in MCF7 human breast cancer cells. 266 75

Insulin receptor substrate 1 (IRS-1) is a major signaling molecule activated by the insulin and insulin-like growth factor I receptors. Recent data obtained in different cell models suggested that in addition to its conventional role as a cytoplasmic signal transducer, IRS-1 has a function in the nuclear compartment. However, the role of nuclear IRS-1 in breast cancer has never been addressed. Here we report that in estrogen receptor alpha (ERalpha)-positive MCF-7 cells, (1) a fraction of IRS-1 was translocated to the nucleus upon 17-beta-estradiol (E2) treatment; (2) E2-dependent nuclear translocation of IRS-1 was blocked with the antiestrogen ICI 182,780; (3) nuclear IRS-1 colocalized and co-precipitated with ERalpha; (4) the IRS-1:ERalpha complex was recruited to the E2-sensitive pS2 gene promoter. Notably, IRS-1 interaction with the pS2 promoter did not occur in ERalpha-negative MDA-MB-231 cells, but was observed in MDA-MB-231 cells retransfected with ERalpha. Transcription reporter assays with E2-sensitive promoters suggested that the presence of IRS-1 inhibits ERalpha activity at estrogen-responsive element-containing DNA. In summary, our data suggested that nuclear IRS-1 interacts with ERalpha and that this interaction might influence ERalpha transcriptional activity.
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PMID:Nuclear insulin receptor substrate 1 interacts with estrogen receptor alpha at ERE promoters. 1531 76

Estrogen receptor alpha (ER) and the insulin-like growth factor I receptor (IGF-IR) pathways are engaged in a functional cross talk in breast cancer, promoting tumor progression and increased resistance to anticancer treatments and radiotherapy. Here, we introduce new mechanisms through which proteins of the IGF-I/IGF-IR signaling pathway may regulate ER function in the absence of ligand. Our results indicate that in ER-positive breast cancer cells, Akt2 modulates ER transcriptional activity at multiple levels, including (i) the regulation of ER expression and its nuclear retention and (ii) the activation of one of its downstream targets, the Forkhead transcription factor FoxO3a. FoxO3a colocalizes and coprecipitates with ER in the nucleus, where it binds to Forkhead-responsive sequences on the ER target pS2/TFF-1 promoter; in addition, FoxO3a silencing leads to an increase of ER transcriptional activity, suggesting a repressive role of the Forkhead transcription factor in ER function. Moreover, 17beta-estradiol upregulates FoxO3a levels, which could represent the basis for an ER-mediated homeostatic mechanism. These findings provide further evidence of the importance of mediators of the growth factor signaling in ER regulation, introducing the Akt2/FoxO3a axis as a pursuable target in therapy for ER-positive breast cancer.
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PMID:Akt2 inhibition enables the forkhead transcription factor FoxO3a to have a repressive role in estrogen receptor alpha transcriptional activity in breast cancer cells. 1993 43