Constitutive Expression and Regulation of Collagenase-3 in Human Breast Cancer Cells

doi:10.1006/mcbr.2000.0215

Molecular Cell Biology Research Communications

Volume 3, Issue 4, April 2000, Pages 218-223

https://doi.org/10.1006/mcbr.2000.0215 Get rights and content

Abstract

Matrix metalloproteinases (MMPs) are a family of secreted or transmembrane proteins that have been implicated in multiple physiological and pathological processes related to extracellular matrix turnover. Recent evidence strongly suggests a role for collagenase-3 (MMP-13) in tumor metastasis and invasion. We report here that collagenase-3 is constitutively expressed in the breast cancer cell line MDA-MB231 (MDA) and outline the molecular mechanism regulating its expression. Functional analysis of the collagenase-3 promoter showed that both the activator protein-1 (AP-1) site and the runt domain (RD) binding site were required for maximal constitutive expression of collagenase-3 in MDA cells. Determination of factors binding to those sites by Northern analysis and transient transfections identified the requirement of Fra-1, c-Jun, and Cbfa1 for basal collagenase-3 promoter activity in MDA cells.

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This chapter surveys our knowledge of the functions of the proteinases expressed in bone. The osteoclast secretes abundant lysosomal cysteine proteinases, especially cathepsin K, and produces some of the neutral proteinases, e.g., matrix metalloproteinase-9. However, osteoblasts and osteocytes, like their related cells, fibroblasts, are able to secrete a host of proteinases, including neutral proteinases such as serine proteinases, plasminogen activators, and metalloproteinases such as matrix metalloproteinase-13, as well as lysosomal proteinases, e.g., cathepsins. Thus, osteoblasts and osteocytes, like fibroblasts, have the capacity not only to synthesize a range of matrix proteins, including type I collagen, but also to remodel their own extracellular matrix via the secretion of a range of proteinases.
miR-590–3p inhibits proliferation and promotes apoptosis by targeting activating transcription factor 3 in human breast cancer cells
2018, Biochimie
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Among 11 selected miRNAs, mir-590, mir-516 b, and mir-504 were found to be significantly downregulated in MDA-MB231 cells compared to MCF-10 A cells (Fig. 1C). Since ATF3 and Runx2 are aberrantly expressed in breast cancer cells, Runx2 is a target gene of ATF3, and both ATF3 and Runx2 play a central role in breast cancer progression and metastasis [10,12–14,18–22,37,38], we aimed to target both ATF3 and Runx2 by miRNAs. It is also known that one miRNA can target more than one gene [24].
We previously reported that ATF3 and Runx2 are involved in breast cancer progression and bone metastasis. The expression of these genes can be controlled by post-transcriptional regulators such as microRNAs (miRNAs). In this study, we identified and validated the functional role of miR-590–3p in human breast cancer cells (MDA-MB231). There was an inverse correlation between the expression of miR-590–3p and its putative target genes, ATF3 and Runx2 in these cells. Overexpression of miR-590–3p decreased the expression of ATF3 and Runx2 at the mRNA and protein levels in MDA-MB231 cells. Luciferase reporter assay identified a direct interaction of 3’ UTRs of ATF3 and Runx2 with miR-590–3p in these cells. Overexpression of miR-590–3p also decreased proliferation and increased apoptosis of breast cancer cells. Based on our results, we suggest that miR-590–3p might have potential clinical applications towards controlling breast cancer progression and bone metastasis.
Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair
2017, Progress in Molecular Biology and Translational Science
Matrix metalloproteinases (MMPs) are the major protease family responsible for the cleavage of the matrisome (global composition of the extracellular matrix (ECM) proteome) and proteins unrelated to the ECM, generating bioactive molecules. These proteins drive ECM remodeling, in association with tissue-specific and cell-anchored inhibitors (TIMPs and RECK, respectively). In the bone, the ECM mediates cell adhesion, mechanotransduction, nucleation of mineralization, and the immobilization of growth factors to protect them from damage or degradation. Since the first description of an MMP in bone tissue, many other MMPs have been identified, as well as their inhibitors. Numerous functions have been assigned to these proteins, including osteoblast/osteocyte differentiation, bone formation, solubilization of the osteoid during bone resorption, osteoclast recruitment and migration, and as a coupling factor in bone remodeling under physiological conditions. In turn, a number of pathologies, associated with imbalanced bone remodeling, arise mainly from MMP overexpression and abnormalities of the ECM, leading to bone osteolysis or bone formation. In this review, we will discuss the functions of MMPs and their inhibitors in bone cells, during bone remodeling, pathological bone resorption (osteoporosis and bone metastasis), bone repair/regeneration, and emergent roles in bone bioengineering.
MMP-13 is one of the critical mediators of the effect of HDAC4 deletion on the skeleton
2016, Bone
Citation Excerpt :
Even though the length of growth plate zones was partially recovered in Hdac4−/−/Mmp13−/− mice, they may not be able to recover the whole bone length. Although Mmp-13 and Mmp-9 are direct targets of Runx2 in bone tissue [28–32] we did not find any effect of deletion of Mmp-13 or Hdac4 on Runx2 gene expression. Interestingly, Mef2c expression level was increased in Hdac4−/− mice and normalized in Hdac4−/−/Mmp13−/− mice.
Histone deacetylase 4 (Hdac4) regulates chondrocyte hypertrophy. Hdac4^−/− mice are runted in size and do not survive to weaning. This phenotype is primarily due to the acceleration of onset of chondrocyte hypertrophy and, as a consequence, inappropriate endochondral mineralization. Previously, we reported that Hdac4 is a repressor of matrix metalloproteinase-13 (Mmp13) transcription, and the absence of Hdac4 leads to increased expression of MMP-13 both in vitro (osteoblastic cells) and in vivo (hypertrophic chondrocytes and trabecular osteoblasts). MMP-13 is thought to be involved in endochondral ossification and bone remodeling. To identify whether the phenotype of Hdac4^−/− mice is due to up-regulation of MMP-13, we generated Hdac4/Mmp13 double knockout mice and determined the ability of deletion of MMP-13 to rescue the Hdac4^−/− mouse phenotype. Mmp13^−/− mice have normal body size. Hdac4^−/−/Mmp13^−/− double knockout mice are significantly heavier and larger than Hdac4^−/− mice, they survive longer, and they recover the thickness of their growth plate zones. In Hdac4^−/−/Mmp13^−/− double knockout mice, alkaline phosphatase (ALP) expression and TRAP-positive osteoclasts were restored (together with an increase in Mmp9 expression) but osteocalcin (OCN) was not. Micro-CT analysis of the tibiae revealed that Hdac4^−/− mice have significantly decreased cortical bone area compared with the wild type mice. In addition, the bone architectural parameter, bone porosity, was significantly decreased in Hdac4^−/− mice. Hdac4^−/−/Mmp13^−/− double knockout mice recover these cortical parameters. Likewise, Hdac4^−/− mice exhibit significantly increased Tb.Th and bone mineral density (BMD) while the Hdac4^−/−/Mmp13^−/− mice significantly recovered these parameters toward normal for this age. Taken together, our findings indicate that the phenotype seen in the Hdac4^−/− mice is partially derived from elevation in MMP-13 and may be due to a bone remodeling disorder caused by overexpression of this enzyme.
Runx2 regulates G protein-coupled signaling pathways to control growth of osteoblast progenitors
2008, Journal of Biological Chemistry
Citation Excerpt :
These genes include tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), procollagen, type VI, α2 (Col6a2) and pan-hematopoietic expression (Phemx)/tetraspannin 32 (Tspan32). Interestingly, Phemx/Tspan32 is a known target gene for RUNX1/AML1 in hematopoietic cells, whereas distinct members of the TIMP and collagen multigene families are Runx2 target genes in other cells and tissues (46–49). Taken together, our genome-wide expression profiling experiments reveal that the C terminus is required for changes in the expression of known target genes.
Runt-related transcription factor 2 (Runx2) controls lineage commitment, proliferation, and anabolic functions of osteoblasts as the subnuclear effector of multiple signaling axes (e.g. transforming growth factor-β/BMP-SMAD, SRC/YES-YAP, and GROUCHO/TLE). Runx2 levels oscillate during the osteoblast cell cycle with maximal levels in G₁. Here we examined what functions and target genes of Runx2 control osteoblast growth. Forced expression of wild type Runx2 suppresses growth of Runx2^-/- osteoprogenitors. Point mutants defective for binding to WW domain or SMAD proteins or the nuclear matrix retain this growth regulatory ability. Hence, key signaling pathways are dispensable for growth control by Runx2. However, mutants defective for DNA binding or C-terminal gene repression/activation functions do not block proliferation. Target gene analysis by Affymetrix expression profiling shows that the C terminus of Runx2 regulates genes involved in G protein-coupled receptor signaling (e.g. Rgs2, Rgs4, Rgs5, Rgs16, Gpr23, Gpr30, Gpr54, Gpr64, and Gna13). We further examined the function of two genes linked to cAMP signaling as follows: Gpr30 that is stimulated and Rgs2 that is down-regulated by Runx2. RNA interference of Gpr30 and forced expression of Rgs2 in each case inhibit osteoblast proliferation. Notwithstanding its growth-suppressive potential, our results surprisingly indicate that Runx2 may sensitize cAMP-related G protein-coupled receptor signaling by activating Gpr30 and repressing Rgs2 gene expression in osteoblasts to increase responsiveness to mitogenic signals.
Expression of MMP-13 in osteoblast cells and rat tibia after exposure to gamma rays or accelerated carbon ions
2007, Physica Medica
Citation Excerpt :
MMP-13 plays an important role in cartilage matrix metabolism and is regulated by Cbfa1 (core binding factor α1, Runx2), which is also important in endochondral ossification and the production of osteoclast differentiation factor. Cbfa1 is required for MMP-13 expression in osteoblastic cells [22]. Only a few mononuclear TRAP-positive cells appear adjacent to the calcified cartilage at the perichondrium in Cbfa1-deficient mice [23,24].
In past research, we found that carbon ion irradiation increased bone volume in rats, and a significant amount of cartilage remained inside the carbon ion-irradiated trabeculae. The amounts of matrix metalloproteinase 13 (MMP-13) mRNA in osteoblast-like MC3T3-E1 cells tended to decrease after carbon ion irradiation. The level of MMP-13 mRNA in non-irradiated cells was stable during the experimental period, but in gamma ray-irradiated cells it tended to increase. When localization of MMP-13 in locally irradiated experimental rats was investigated, it was found in the marginal trabeculae in both non-irradiated and gamma ray-irradiated animals. MMP-13 was detected in osteoid and neogenetic bone in the trabeculae surface. The trabeculae in carbon ion-irradiated bone remained cartilaginous. Carbon ion-irradiated rats exhibited weak expression of MMP-13 around the cartilage inside the trabeculae. We conclude that carbon ion irradiation reduced expression of MMP-13, thus suppressing both chondrocyte maturation and cartilage resorption. Increases in hyperplasia of the bone trabeculae and of bone volume were caused by ongoing bone addition and calcification in the absence of sufficient cartilage resorption.

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Regular ArticleConstitutive Expression and Regulation of Collagenase-3 in Human Breast Cancer Cells

Abstract

J. Biol. Chem.

J. Invest. Dermatol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Genomics

J. Biol. Chem.

J. Biol. Chem.

Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

Cancer Metast. Rev.

J. Histochem. Cytochem.

Cancer Res.

Regular Article
Constitutive Expression and Regulation of Collagenase-3 in Human Breast Cancer Cells