Mammalian stanniocalcins and cancer.

Chang, Andy; Jellinek, Derek; Reddel, Roger R.

doi:10.1677/erc.0.0100359

Cited by 144 publications

(146 citation statements)

References 98 publications

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“…Ataxin 1 is detected in various brain regions and in non-neuronal tissues, such as the heart, skeletal muscle and liver (Servadio et al, 1995;Tsai et al, 2004). Stanniocalcin1, encoded by STC1 gene, is a glycoprotein hormone and it has a role in many physiological processes, including bone development, reproduction, wound healing, angiogenesis and modulation of inflammatory response (Ishibashi and Imai, 2002;Chang et al, 2003). The STC1 gene is expressed in a wide variety of tissues, including the kidney, prostate, thyroid, bone and ovary (Chang et al, 1995;Olsen et al, 1996;Varghese et al, 1998).…”

Section: Atxn1 and Stc1 Are Targets Of Mir-101bmentioning

confidence: 99%

Regulation of microRNA expression by HMGA1 proteins

et al. 2009

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The High Mobility Group proteins HMGA1 are nuclear architectural factors that play a critical role in a wide range of biological processes. Since recent studies have identified the microRNAs (miRNAs) as important regulators of gene expression, modulating critical cellular functions such as proliferation, apoptosis and differentiation, the aim of our work was to identify the miRNAs that are physiologically regulated by HMGA1 proteins. To this purpose, we have analysed the miRNA expression profile of mouse embryonic fibroblasts (MEFs) carrying two, one or no Hmga1 functional alleles using a microarray (miRNA microarray). By this approach, we found a miRNA expression profile that differentiates Hmga1-null MEFs from the wild-type ones. In particular, a significant decrease in miR-196a-2, miR-101b, miR-331 and miR-29a was detected in homozygous Hmga1-knockout MEFs in comparison with wild-type cells. Consistently, these miRNAs are downregulated in most of the analysed tissues of Hmga1-null mice in comparison with the wild-type mice. ChIP assay shows that HMGA1 is able to bind regions upstream of these miRNAs. Moreover, we identified the HMGA2 gene product as a putative target of miR-196a-2, suggesting that HMGA1 proteins are able to downregulate the expression of the other member of the HMGA family through the regulation of the miR-196a-2 expression. Finally, ATXN1 and STC1 gene products have been identified as targets of miR-101b. Therefore, it is reasonable to hypothesize that HMGA1 proteins are involved in several functions by regulating miRNA expression.

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Section: Atxn1 and Stc1 Are Targets Of Mir-101bmentioning

confidence: 99%

Regulation of microRNA expression by HMGA1 proteins

et al. 2009

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“…S6). Further knockdown of this transcript was not achievable in stable cell lines, perhaps owing to the pro-proliferative function of this gene (12). Importantly, the stable knockdown of STC1 did not alter PR-B expression in either cell line (Fig.…”

Section: Hormone-independent Pr Target Genes Contribute To Breast Cancermentioning

confidence: 95%

“…1C and S1), we investigated the regulation of selected endogenous gene targets by unliganded PR. Stanniocalcin 1 (STC1), a peptide hormone overexpressed in breast cancers, has been shown to increase cell metabolism and tumor growth (12). Gene array analysis of T47D breast cancer cells demonstrated that STC1 expression is induced by the forced expression of unliganded PR-A or PR-B (7).…”

Section: Sumoylation Of Pr-b Represses Transcription Of a Subset Of Tmentioning

confidence: 99%

Protein kinases mediate ligand-independent derepression of sumoylated progesterone receptors in breast cancer cells

Daniel

Lange

2009

Proc. Natl. Acad. Sci. U.S.A.

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In advanced breast tumors, protein kinases are upregulated and steroid hormone receptors often function independently of ligand. Herein, we explored mechanisms of ligand-independent progesterone receptor (PR) activity. We showed previously that growth factorinduced phosphorylation of PR Ser-294 blocks PR Lys-388 sumoylation. SUMO-deficient mutant PR-B (K388R) thus provides a model receptor for the study of PR function in the context of high kinase activities. T47D cells stably expressing K388R PR-B exhibited increased ligand-independent proliferation and growth in soft agar relative to cells expressing wt PR-B or phospho-mutant (sumoylated) S294A PR-B. Expression of selected PR target genes (HB-EGF, IRS-1, and STC1) was significantly elevated in cells containing desumoylated (K388R) PR-B. Basal PR transcriptional activity occurred independently of progestins, was increased by activated CDK2, and attenuated by RU486. Notably, ChIP assays demonstrated that K388R PR-B and SRC1 were constitutively recruited to the STC1 promoter in the absence of progestin; PR Lys-388 sumoylation was required for HDAC3 recruitment. Knock-down of STC1 inhibited proliferation of cells expressing K388R PR-B. These data suggest a mechanism whereby phosphorylated, and thus desumoylated, PRs mediate increased expression of growth promoting genes. Our data explain why breast cancer models often remain insensitive to progestins, but are growth-inhibited by antiprogestins, and underscore the need to target PR-B and associated kinase activities as part of breast cancer therapy.HDAC ͉ phosphorylation ͉ sumoylation P rogesterone receptors (PR) mediate lobulo-alveolar proliferation during breast development and contribute to breast cancer progression, in part by synergizing with peptide growth factors (1-3). Regulation of PR activity occurs via the integration of ligand activated rapid signaling events and transcriptional activation (4). Peptide growth factors diminish the requirement for steroid hormone ligands by activation of protein kinases that directly target PR and its co-activators (i.e., a function of rapid signaling events). For example, direct phosphorylation of PR by MAPK or CDK2 alters transcriptional activity in part by modulating other posttranslational modifications including ubiquitination and sumoylation (3,5). Crosstalk between growth factor pathways and steroid receptors provides an exquisite mechanism for mammary epithelial cells to sense a dynamic range of hormone concentrations and selectively regulate specific promoters.Sumoylation of steroid hormone receptors represses transcriptional activity (6). We showed that EGF and protein kinasedependent (MAPK, CDK2) phosphorylation of PR-B on Ser-294 blocks sumoylation of PR Lys-388 (5). Undersumoylated receptors respond to low concentrations of ligand and are transcriptionally hyperactive at a subset of PRE (progesterone response element) containing target genes (HB-EGF). Sumoylation of PR is thus a key modulator of both the progesterone/PR dose-response curve and PR target gene ...

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“…Many independent studies have reported alterations in STC1 expression levels in response to different stresses (Iyer et al, 1999;Sheikh-Hamad et al, 2000;Chang et al, 2003), but the significance of such changes in expression has hitherto been unknown. In light of our findings, it appears that STC1 functions in response to cellular stress to control the cell death vs survival decision, and this is consistent with two recent studies.…”

Section: Regulation Of Oxidative Stress Response By Stc1mentioning

confidence: 99%

“…Stanniocalcin-1 (STC1) is a glycoprotein that has been highly conserved from fish to mammals (Chang et al, 2003). In fish, it functions as a classic hormone that is secreted from endocrine glands, the Corpuscles of Stannius, in response to hypercalcemia and inhibits uptake of calcium through the gills and gut (Wagner et al, 1988;Sundell et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Stanniocalcin-1 acts in a negative feedback loop in the prosurvival ERK1/2 signaling pathway during oxidative stress

2009

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Mammalian Stanniocalcin-1 (STC1) is a glycoprotein that has been implicated in various biological processes including angiogenesis. Aberrant STC1 expression has been reported in breast, ovarian and prostate cancers, but the significance of this is not well understood. Here, we report that oxidative stress caused a 40-fold increase in STC1 levels in mouse embryo fibroblasts (MEFs). STC1À/À MEFs were resistant to growth inhibition and cell death induced by H 2 O 2 or by 20% O 2 (which is hyperoxic for most mammalian cells); this is the first phenotype reported for STC1-null cells. STC1À/À cells had higher levels of activated MEK and ERK1/2 than their wild-type (WT) counterparts, and these levels were all reduced by stable expression of exogenous STC1 in STC1À/À cells. Furthermore, pharmacological inhibition by PD98059 or UO126 of MEK and therefore of ERK1/2 activation restored sensitivity of STC1À/À cells to oxidative stress. We also found that H 2 O 2 -induced STC1 expression in WT cells was abolished by inhibition of ERK1/2 activation. Thus, the ERK1/2 signaling pathway upregulates STC1 expression, which in turn downregulates the level of activated MEK and consequently ERK1/2 in a novel negative feedback loop. Therefore, STC1 expression downregulates prosurvival ERK1/2 signaling and reduces survival under conditions of oxidative stress.

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Mammalian stanniocalcins and cancer.

Cited by 144 publications

References 98 publications

Regulation of microRNA expression by HMGA1 proteins

Regulation of microRNA expression by HMGA1 proteins

Protein kinases mediate ligand-independent derepression of sumoylated progesterone receptors in breast cancer cells

Stanniocalcin-1 acts in a negative feedback loop in the prosurvival ERK1/2 signaling pathway during oxidative stress

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