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GSE8322
Mus musculus
11 Downloadable Samples
Description
We recently found that the endoplasmic reticulum (ER) stress response (ERSR) is activated in surviving cardiac myocytes in a mouse model of in vivo myocardial infarction. ATF6 is an ER stress-activated transcription factor that induces ERSR genes, some of which encode proteins that may protect against ischemic damage. However, few ERSR genes have been identified in the heart, and there have been no gene expression profiling studies of ATF6-inducible genes, in vivo. We previously generated transgenic (TG) mice that express tamoxifen-activated ATF6, ATF6-MER, in the heart; ATF6-MER conferred tamoxifen-dependent ATF6 activation and protection from ischemic damage. To understand of the mechanism of ATF6-mediated cardioprotection, gene expression profiling of ATF6-MER TG mouse hearts was performed. Activated ATF6 changed expression levels of 1,162 genes in the heart; of the 775 ATF6-inducible genes, only 23 are known ERSR genes. One of the genes not expected to be induced by ATF6 is modulatory calcinuerin-interacting protein-1 (MCIP1). MCIP1 is induced in a calcineurin/NFAT-dependent manner during myocardial hypertrophy and it can feedback inhibit cardiomyocyte growth. We found that MCIP1 expression in cultured cardiomyocytes was increased by the prototypical ER stresser, tunicamycin (TM), or by simulated ischemia. Moreover, infecting cardiomyocytes with adenovirus encoding activated ATF6 induced MCIP1 expression and inhibited myocyte growth in response to the alpha 1-adrenergic agonist, phenylephrine. These results suggest that MCIP1 can be induced in the heart by ER stresses, such as ischemia. Moreover, b integrating hypertrophy and ER stress, MCIP-modulated myocyte growth may help rejuvenate nascent ER protein folding, which could contribute to protection from ischemic damage.
Publication Title
Coordination of growth and endoplasmic reticulum stress signaling by regulator of calcineurin 1 (RCAN1), a novel ATF6-inducible gene.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Mus musculus
- 6 Downloadable Samples
Description
PTEN loss or PI3K/AKT signaling pathway activation correlates with human prostate cancer progression and metastasis. However, in preclinical murine models, deletion of Pten alone fails to mimic the significant metastatic burden that frequently accompanies the end stage of human disease. To identify additional pathway alterations that cooperate with PTEN loss in prostate cancer progression, we surveyed human prostate cancer tissue microarrays and found that the RAS/MAPK pathway is significantly elevated both in primary and metastatic lesions. In an attempt to model this event, we crossed conditional activatable K-rasG12D/WT mice with the prostate conditional Pten deletion model we previously generated. Although RAS activation alone cannot initiate prostate cancer development, it significantly accelerated progression caused by PTEN loss, accompanied by epithelial-to-mesenchymal transition (EMT) and macrometastasis with 100% penitence. A novel stem/progenitor subpopulation with mesenchymal characteristics was isolated from the compound mutant prostates, which was highly metastatic upon orthotopic transplantation. Importantly, inhibition of RAS/MAPK signaling by PD325901, a MEK inhibitor, significantly reduced the metastatic progression initiated from transplanted stem/progenitor cells. Collectively, these data indicate that activation of RAS/MAPK signaling serves as a potentiating second hit to alteration of the PTEN/PI3K/AKT axis and co-targeting both pathways is highly effective in preventing the development of metastatic prostate cancers.
Publication Title
Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells.
Sample Metadata Fields
Specimen part
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