Tumor Suppressor p53 Protein Is a New Target for the Metastasis-associated Mts1/S100A4 Protein

Grigorian, Mariam; Andresen, Susanne; Tulchinsky, Eugene; Kriajevska, Marina; Carlberg, Charlotte; Kruse, Charlotte; Cohn, Martin A.; Ambartsumian, Noona; Christensen, Annette; Selivanova, Galina; Lukanidin, Eugene

doi:10.1074/jbc.m010231200

Cited by 279 publications

(261 citation statements)

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“…Extracellular S100A4 Modulates Transcription of p53-dependent Genes-Previously, we demonstrated that intracellular S100A4 binds and regulates p53 function (18). Here we tested whether the recombinant S100A4 protein added to cultured VMR cells may influence activity of wild type p53.…”

Section: S100a4(mts1) In Tumor-stroma Interactionmentioning

confidence: 97%

“…Interaction of S100A4 with intracellular target proteins, non-muscle myosin heavy chain and liprin␤1, might be responsible for tumor cell adhesion and motility (15)(16)(17). The tumor suppressor p53, another S100A4 target protein (18), is deeply involved in various pathways implicated in tumor progression (apoptosis, angiogenesis, cell differentiation, and motility).…”

Section: Figmentioning

confidence: 99%

“…S100A4 interacts with the tumor suppressor protein p53 and regulates its transactivational function. As a consequence of this interaction, differential modulation of p53-target genes expression occurs in a cell-specific manner (18).…”

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Functional Significance of Metastasis-inducing S100A4(Mts1) in Tumor-Stroma Interplay

Schmidt-Hansen

Klingelhöfer

Grum-Schwensen

et al. 2004

Journal of Biological Chemistry

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Causal implication of S100A4 in inducing metastases was convincingly shown previously. However, the mechanisms that associate S100A4 with tumor progression are not well understood. S100A4 protein, as a typical member of the S100 family, exhibits dual, intracellular and extracellular, functions. This work is focused on the extracellular function of S100A4, in particular its involvement in tumor-stroma interplay in VMR (mouse adenocarcinoma cell line) tumor cells, which exhibit stroma-dependent metastatic phenotype. We demonstrated the reciprocal influence of tumor and stroma cells where tumor cells stimulate S100A4 secretion from fibroblasts in culture. In turn, extracellular S100A4 modifies the cytoskeleton and focal adhesions and triggers several other events in tumor cells. We found stabilization of the tumor suppressor protein p53 and modulation of its function. In particular, extracellular S100A4 down-regulates the pro-apoptotic bax and the angiogenesis inhibitor thrombospondin-1 genes. For the first time, we demonstrate here that the S100A4 protein added to the extracellular space strongly stimulates proteolytic activity of VMR cells. This activity most probably is associated with matrix metalloproteinases and, in particular, with matrix metalloproteinase-13. Finally, the application of the recombinant S100A4 protein confers stroma-independent metastatic phenotype on VMR tumor cells. In conclusion, our results indicate that metastasis-inducing S100A4 protein plays a pivotal role in the tumor-stroma environment. S100A4 released either by tumor or stroma cells triggers pro-metastatic cascades in tumor cells.Metastatic dissemination of cancer cells results in incurable disease and becomes one of the leading causes of cancer patient deaths. Studies on genes and their protein products involved in this process are of great importance.Causal implication of S100A4 (mts1, CAPL, pEL98, Calvasculin, p9Ka, and FSP1) in metastatic tumor progression was demonstrated by several approaches. Transfection of rodent and human non-metastatic tumor cell lines with S100A4 converts their phenotype to metastatic cells, and contrariwise, the antisense-and ribozyme-mediated mts1-inactivation abolish the metastatic potential of metastatic tumor cells (1-4). Tumors developed in transgenic mice bearing exogenous S100A4 gene acquired metastatic phenotype (5, 6). The tight association of S100A4 with metastasis allows us to rate it among the most reliable prognostic markers. A high level of S100A4 in various types of cancers (breast, esophageal, gastric, colorectal, bladder, gallbladder, and lung) correlates with unfavorable prognosis and lethality (7-11). S100A4 belongs to the S100 family of Ca 2ϩ -binding proteins that comprises 20 members. They are involved in the regulation of various important cellular functions such as cell growth, cell-cell communication, energy metabolism, contraction, neurite outgrowth, and cell motility (for review see Refs. 12-14). S100A4 protein, as a typical member of the S100 family, exerts dual, intracellul...

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Section: S100a4(mts1) In Tumor-stroma Interactionmentioning

confidence: 97%

Section: Figmentioning

confidence: 99%

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Functional Significance of Metastasis-inducing S100A4(Mts1) in Tumor-Stroma Interplay

Schmidt-Hansen

Klingelhöfer

Grum-Schwensen

et al. 2004

Journal of Biological Chemistry

Self Cite

131

136

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“…The poor outlook for cancer patients with elevated expression of S100A4 is likely to be due to the ability of S100A4 to induce a metastatic phenotype; however, the mechanism of the strong metastasisinducing properties of S100A4 is not known. S100A4 has been reported to interact with a number of protein targets, at least in vitro, namely nonmuscle tropomyosin (Takenaga et al, 1994), nonmuscle myosin A heavy chain (Kriajevska et al, 1994;Ford and Zain, 1995), p53 (Grigorian et al, 2001), liprin b1 (Kriajevska et al, 2002) and methionine aminopeptidase 2 (Endo et al, 2002). S100A4 also self-associates to form a homodimer as shown by its NMR structure (Vallely et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Mutually antagonistic actions of S100A4 and S100A1 on normal and metastatic phenotypes

et al. 2004

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Increased levels of the homodimeric calcium-binding protein, S100A4, have been shown to cause a metastatic phenotype in at least three independent model systems of breast cancer and its presence in carcinoma cells has been shown to be associated with a reduction in the survival of patients suffering from a range of different cancers. S100A4 has been shown to interact in vitro with another member of the S100 family of proteins, S100A1. The purpose of the present study was to find out whether S100A1 could affect S100A4 function. Fluorescence resonance energy transfer was used to show the interaction of S100A4 and S100A1 in living cells and the binding affinities between S100A4 and S100A1 were determined using a biosensor. S100A1 reduced the S100A4 inhibition of nonmuscle myosin A self-association and phosphorylation in vitro. S100A1 reduced S100A4 induced motility and growth in soft agar and metastasis in vivo. The results show for the first time that interactions between different S100 proteins can affect cancer-related activity, and that the presence of S100A1 protein in carcinoma cells might modulate the effect of S100A4 on their metastatic abilities.

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“…16 Moreover, S100A4 binds to the tumor suppressor p53 and modulates its transcriptional activity. 17 Extracellular S100A4 activates expression of several matrix metalloproteinases, thereby enabling cell invasion into adjacent tissues and facilitating angiogenesis. 18,19 High levels of S100A4 correlate with reduced patient survival and poor prognosis in several types of cancer.…”

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confidence: 99%

Diagnostic and Prognostic Value of Metastasis Inducer S100A4 Transcripts in Plasma of Colon, Rectal, and Gastric Cancer Patients

Stein

Burock

Herrmann

et al. 2011

The Journal of Molecular Diagnostics

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Early detection of tumors and metastases is critical for improving treatment strategies and patient outcomes.The development of molecular markers and simple tests that are clinically applicable for detection, prognostication, and therapy monitoring is strongly needed. The gene S100A4 has long been known to act as a metastasis inducer. High S100A4 levels in the primary tumor are prognostic for metachronous metastasis and correlate with reduced patient survival. We provide, for the first time, a plasma-based assay for transcript quantification of S100A4 in gastrointestinal patients' plasma. We conducted a study to define the diagnostic and prognostic power of S100A4 transcripts using 466 plasma samples from colon, rectal, and gastric cancer patients. Plasma was separated, RNA was isolated, and S100A4 mRNA was determined by quantitative RT-PCR. S100A4 transcripts were increased in cancer patients of each entity (P < 0.0001) and all disease stages (P < 0.05), compared with tumor-free volunteers (sensitivities of 96%, 74%, and 90% and specificities of 59%, 82%, and 71%, for colon, rectal, and gastric cancer patients, respectively). Prospectively analyzed follow-up patients who later experienced metastasis showed higher S100A4 levels than follow-up patients without metastasis. Disease-free survival was decreased in high S100A4-expressing follow-up colorectal cancer patients (P ‫؍‬ 0.013). In summary, we developed a method for quantitative S100A4 transcript determination in plasma that allows clinical application routinely. We demonstrated the diagnostic and prognostic potential of this method for early defining cancer staging and patients' risk for metastasis. Gastrointestinal cancers, such as colon, rectal, and gastric cancers, belong to the malignancies with the highest incidences and mortalities worldwide. Approximately 90% of all cancer deaths arise from the metastatic dissemination of primary tumors. 1,2 To date, primary colorectal carcinomas cannot be sufficiently distinguished with respect to clinical outcome parameters, such as local recurrence and metastasis, by means of conventional clinical and histopathological/immunhistochemical examination. The tumor-node-metastasis (TNM) classification represents the main tool for identifying prognostic differences among patients with early-stage colorectal cancer. 3 This is also true for gastric cancer, currently evaluated by histological staging as well. 4 Therefore, early detection of tumors and metastasis is critical for improving treatment strategies and patient outcomes. There is a clear need for development of molecular markers and of simple tests that can clinically be used for detection, prognostication, and therapy monitoring of cancer. A noninvasive blood test for the early identification of high-risk cancer patients is therefore of special interest. Circulating nucleic acids and, in particular, cell-free mRNA can be detected in plasma and permit plasma-based expression profiling. 5-9 It was recently reported that extracellular plasma RNA from colon cancer pa...

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Tumor Suppressor p53 Protein Is a New Target for the Metastasis-associated Mts1/S100A4 Protein

Cited by 279 publications

References 40 publications

Functional Significance of Metastasis-inducing S100A4(Mts1) in Tumor-Stroma Interplay

Functional Significance of Metastasis-inducing S100A4(Mts1) in Tumor-Stroma Interplay

Mutually antagonistic actions of S100A4 and S100A1 on normal and metastatic phenotypes

Diagnostic and Prognostic Value of Metastasis Inducer S100A4 Transcripts in Plasma of Colon, Rectal, and Gastric Cancer Patients

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