Trps1 regulates proliferation and apoptosis of chondrocytes through Stat3 signaling

Suemoto, Hiroki; Muragaki, Yasuteru; Nishioka, K; Sato, Misako; Ooshima, Akira; Itoh, Shousaku; Hatamura, Ikuji; Ozaki, Michitaka; Braun, Attila; Gustafsson, Erika; Fässler, Reinhard

doi:10.1016/j.ydbio.2007.10.001

Cited by 114 publications

(127 citation statements)

References 31 publications

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“…In early hair follicle progenitors, TRPS1 is a transcriptional activator of genes that inhibit Wnt signaling (56), whereas it is a repressor of RUNX2, a gene important for osteoclast differentiation and maturation (57). Moreover, in odontoblast development, Trsp1 is an inhibitor of Dspp expression (58), whereas in chondrocytes, Trps1 controls proliferation and survival by repressing Stat3 expression (59). In pathological conditions, TRPS1 represses the expression of ZEB2, a component of the EMT pathway (52).…”

Section: Discussionmentioning

confidence: 99%

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Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Rangel

Lee

Ban

et al. 2016

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

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Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1. Down-regulation of TRPS1 in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression of SERPINE1 and SERPINB2 and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.Sleeping Beauty | breast cancer | TRPS1 | metastasis | tumor suppressors B reast cancer is the second leading cause of cancer-related deaths in the United States. The Cancer Genome Atlas (TCGA) network has classified breast cancer into four main subtypes: luminal A, luminal B, HER2+, and basal-like (1-5). Basal-like or triplenegative breast cancer (TNBC) constitutes 10-20% of all breast cancers and has a higher rate of distal recurrence and a poorer prognosis than other breast cancer subtypes. Less than 30% of women with metastatic TNBC survive 5 y and almost all die from their disease despite adjuvant chemotherapy (1, 3-5). Mutations, rearrangements, or deletions in highly penetrant genes such as BRCA1, BRCA2, TP53, CDH1, STK11, and PTEN are important drivers of TNBC (6-8). PTEN is a dual-specificity phosphatase that antagonizes the PI3K/AKT pathway through its lipid phosphatase activity and negatively regulates the MAPK pathway through its protein phosphatase activity (9, 10). Mutations in PTEN drive epithelial-mesenchymal transition (EMT) and promote metastasis in TNBC (11-13). Similarly, in mice, heterozygous deletion of Pten induces mammary tumors with basal-like characteristics (14)(15)(16)(17).Despite all of the cancer genome-sequencing efforts, there is still an incomplete understanding of the genes and genetic networks driving TNBC. New technologies that would provide a more complete understanding of the genetics of TNBC are still needed to deconvolute the complexity of this deadly cancer. Our laboratory and others have pioneered the use of transposon mutagenesis in mice as a tool for cancer gene discovery (18-26). Transposons induce cancer by randomly inserting into the mouse genome, mutating, and disrupting potential cancer genes. Transposon insertions in tumors thus serve as molecular tags for the high-throughput cloning and identification of cancer genes. In addition, because transposon insertions are PCR-amplified before they are sequenced, insertional mutations in cancer genes that are present in only a small fraction of tumor cells can be identified. Transposon mutagenesis can thus identify genes that are functioning at th...

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Section: Discussionmentioning

confidence: 99%

“…Because TRPS1 represses transcription from GATA-containing binding sites (43,(56)(57)(58)(59), we searched for conserved GATA sites in the promoter regions of SERPINE1 and SERPINB2. We then designed oligonucleotides specific for these binding sites.…”

Section: Trps1 Regulates the Expression Of Multiple Genes In The Emtmentioning

confidence: 99%

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Rangel

Lee

Ban

et al. 2016

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

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“…Previous studies have revealed a role for TRPS1 in the differentiation of chondrocytes (19,20,25,60), but no studies have proposed a role in osteoblasts. Such a role is, however, consistent with the observation that Trps1 is expressed in the mandible (17), a bone that is made by intramembranous ossification.…”

Section: Discussionmentioning

confidence: 99%

“…Mice engineered to express TRPS1 with a GATA-binding domain deletion (Trps1 ⌬GT mice) have a stronger phenotype in the heterozygous state than mice heterozygous for a null allele of Trps1 (20,24). Trps1…”

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confidence: 99%

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Identification of the GATA Factor TRPS1 as a Repressor of the Osteocalcin Promoter

Piscopo

Johansen

Derynck

2009

Journal of Biological Chemistry

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A proteomic analysis of proteins bound to the osteocalcin OSE2 sequence of the mouse osteocalcin promoter identified TRPS1 as a regulator of osteocalcin transcription. Mutations in the TRPS1 gene are responsible for human tricho-rhino-phalangeal syndrome, which is characterized by skeletal and craniofacial abnormalities. TRPS1 has been shown to bind regulatory promoter sequences containing GATA consensus binding sites and to repress transcription of genes involved in chondrocyte differentiation. Here we show that TRPS1 can directly bind the osteocalcin promoter in the presence or absence of Runx2. TRPS1 binds through a GATA binding sequence in the proximal promoter of the osteocalcin gene. The GATA binding site is conserved in mice, humans, and rats, although its location and orientation are not. Mutation of the mouse or human GATA binding sequence abrogates binding of TRPS1 to the osteocalcin promoter. We show that TRPS1 is expressed in osteosarcoma cells and upon induction of osteoblast differentiation in primary mouse bone marrow stromal cells and that TRPS1 regulates the expression of osteocalcin in both cell types. The expression of TRPS1 modulates mineralized bone matrix formation in differentiating osteoblast cells. These data suggest a role for TRPS1 in osteoblast differentiation, in addition to its previously described role in chondrogenesis.Runx2, previously described as CBFA1, OSF2, AML3, or PEPB2␣A, is a runt homology domain transcription factor and plays a key role in driving osteoblast differentiation. Runx2 expression, which occurs in differentiating and mature osteoblasts, is essential for bone formation, as illustrated by the phenotype of Runx2-deficient mice, which lack osteoblasts and have skeletons that are primarily composed of immature chondrocytes (1-3). Haploinsufficiency for RUNX2 in humans results in cleidocranial dysplasia, a syndrome that is characterized by delayed endochondral and intramembranous ossification (4). Runx2 transactivates genes involved in the deposition of bone matrix, e.g. those encoding osteocalcin, collagen IA1, osteopontin, and matrix metalloproteinase 13 (MMP13), and regulation of osteoclastogenesis, e.g. the genes encoding RankL and osteoprotegerin (reviewed in Ref. 5). Although Runx2 is expressed in cells of the osteoblast lineage throughout skeletal development, its levels increase only 1.5-2-fold as preosteoblasts differentiate into mature osteoblasts. Furthermore, the amount of Runx2 bound to target promoters, as measured by chromatin immunoprecipitation, is relatively unchanged throughout differentiation (6), yet the targets it regulates have distinct patterns of expression. These observations suggest that the regulation of Runx2 activity, either by post-translational modification or by the binding of co-regulators, plays a substantial role in defining the Runx2-mediated activation of target genes. Various proteins have been shown to interact with Runx2 and modulate its activity, including Smad3, CREB 2 -binding protein (CBP) HES1, Groucho/TLE, and histone d...

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Late manifestations of tricho‐rhino‐pharangeal syndrome in a patient: Expanded skeletal phenotype in adulthood

Izumi

Takagi

Parikh

et al. 2010

American J of Med Genetics Pt A

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Trps1 regulates proliferation and apoptosis of chondrocytes through Stat3 signaling

Cited by 114 publications

References 31 publications

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Identification of the GATA Factor TRPS1 as a Repressor of the Osteocalcin Promoter

Late manifestations of tricho‐rhino‐pharangeal syndrome in a patient: Expanded skeletal phenotype in adulthood

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