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At least 1,009 records · Page 56Linked to original sources
PubMed1996

The chicken malic enzyme gene: structural organization and identification of triiodothyronine response elements in the 5'-flanking DNA.

In vivo, feeding stimulates and starvation inhibits transcription of the malic enzyme gene. In chick-embryo hepatocytes in culture, triiodothyronine (T3) stimulates and glucagon inhibits transcription of this gene. As a first step in the characterization of the involved regulatory mechanisms, fragments of genomic DNA spanning the structural and 5'-flanking regions of the chicken malic enzyme gene were cloned. The coding region of the gene is organized into 14 exons and 13 introns and is greater than 106 kb in length. The size of the gene, the number and lengths of the exons, and positions at which introns are inserted into the coding regions are virtually identical in the chicken and rat genes. When transiently transfected into chick-embryo hepatocytes, 5800 bp of 5'-flanking DNA conferred T3 responsiveness to a linked chloramphenicol acetyltransferase (CAT) reporter gene. Using deletion and site-specific mutations of 5'-flanking DNA, we identified a complex T3 response unit that contains one major T3 response element (T3RE) and several minor ones. The major element contains two degenerate copies of the hexamer, RGGWMA, separated by 4 bp and was a strong repressor in the absence of ligand. Endogenous levels of T3 receptor are sufficient to allow the T3 response elements in the upstream region of the malic enzyme gene to confer responsiveness to T3, suggesting that they are physiologically relevant.

Animals↗
PubMed1996

A functional Rev-erb alpha responsive element located in the human Rev-erb alpha promoter mediates a repressing activity.

Rev-erb alpha belongs to the nuclear receptor superfamily, which contains receptors for steroids, thyroid hormones, retinoic acid, and vitamin D, as well as "orphan" receptors. No ligand has been found for Rev-erb alpha to date, making it one of these orphan receptors. Similar to some other orphan receptors, Rev-erb alpha has been shown to bind DNA as a monomer on a specific sequence called a Rev-erb alpah responsive element (RevRE), but its transcriptional activity remains unclear. In this paper, we characterize a functional RevRE located in the human Rev-erb alpha promoter itself. We also present evidence that (i) Rev-erb alpha mediates transcriptional repression of its own promoter in vitro, (ii) this repressing effect strictly depends on the binding of Rev-erb alpha to its responsive element and is transferable to a heterologous promoter; and (iii) Rev-erb alpha binds to this responsive sequence as a homodimer.

Base Sequence↗
PubMed1995

An N-terminal deletion mutant of estrogen receptor exhibits increased synergism with upstream activators and enhanced binding to the estrogen response element.

To study the role of the N-terminal region of the estrogen receptor (ER) in transcription activation and in DNA binding, we constructed a mutant of the Xenopus laevis ER which lacks amino acids 1-159 (XER160/586). In transient transfections, XER160/586 exhibited < 10% of the activity of wild-type XER on a synthetic promoter containing two estrogen response elements (EREs). To examine transcriptional synergism by XER and by XER160/586, we determined the activity of promoters containing EREs and binding sites for either the vitellogenin activator, NF1, or AP1 upstream activator protein. For the three promoters transcription by XER was 2.8-fold greater than expected for additive activities, and transcription by XER160/586 was 6.2-fold greater. These data demonstrate that an upstream activator protein bound near the promoter can partially compensate for the loss of the internal N-terminal (AF1) transactivation domain in XER160/586. Using a promoter interference assay to study the intracellular interaction between ER and the estrogen response element, we found that XER160/586 exhibited a significant increase in affinity for the ERE. Its low basal activity and enhanced affinity for the ERE make XER160/586 an effective dominant negative mutant. When co-expressed with wild-type XER at 1:1 and 5:1 ratios, XER160/586 suppressed the activity of wild-type XER by 57% and > 80%, respectively.

Animals↗
PubMed1995

Repression of protein kinase C and stimulation of cyclic AMP response elements by fumonisin, a fungal encoded toxin which is a carcinogen.

Fusarium moniliforme (FM) is a major fungal pathogen of corn and is involved with stalk rot disease. FM is widely spread throughout the world, including the United States. Most strains of FM produce several mycotoxins, the most prominent of which is called fumonisin. Recent epidemiological studies indicated that ingestion of fumonisin correlates with a higher incidence of esophageal cancer in Southern and Northern Africa and China. Furthermore, fumonisin causes a neurodegenerative disease in horses, induces hepatic cancer in rats, and induces pulmonary edema in swine. Considering that high levels of fumonisin have been detected in healthy and diseased corn grown in the United States, fumonisin may pose a health threat to humans and livestock animals. Structurally, fumonisin resembles sphingolipids which are present in the membranes of animal and plant cells. At the present time, very little is known concerning the mechanism by which fumonisin elicits its carcinogenic effect. Our studies indicate that fumonisin represses expression of protein kinase C and AP-1-dependent transcription. In contrast, fumonisin stimulated a simple promoter containing a single cyclic AMP response element. Since fumonisin did not alter protein kinase A activity, it appears that cyclic AMP response element activation was independent of protein kinase A. It is hypothesized that the ability of fumonisin to alter signal transduction pathways plays a role in carcinogenesis.

Animals↗
PubMed1998

A newly identified response element in the CD95 ligand promoter contributes to optimal inducibility in activated T lymphocytes.

Inducible expression of CD95 ligand on activated T lymphocytes contributes to both cytotoxic effector mechanisms and peripheral T cell homeostasis. To understand better the transcriptional events that regulate this expression, we have examined the CD95 ligand promoter to determine which regions are required for its induced activity following T cell stimulation. We report here the identification of a new response element within the promoter that is required for its optimal function in activated Jurkat T cells. This region is bound by proteins contained in nuclear extracts of activated, but not resting, T cells. Multimerization of this sequence independently drives transcription in response to T cell activation, while mutation of it substantially decreases inducible promoter activity. Finally, we provide evidence that T cell activation-induced transcription of the CD95 ligand gene is regulated coordinately by this response element together with two previously defined sites for nuclear factor of activated T cells (NFAT).

DNA-Binding Proteins↗
PubMed1997

Further characterisation of the p53 responsive element--identification of new candidate genes for trans-activation by p53.

The p53 protein is known to trans-activate a number of genes by specific binding to a consensus sequence containing two decamers of the type: PuPuPuCA/TT/AGPyPyPy. In order to identify new p53 trans-activated genes, we defined a set of criteria for computer search of p53-responsive elements. Based on experimental data, we proposed an extended consensus sequence composed of the two decamers of the El-Deiry consensus sequence flanked by two additional ones. A maximum of 3 bp substitutions was accepted for the two decamers of the El-Deiry consensus sequence, as well as for each additional decamer, except when the two decamers of the El-Deiry consensus sequence are contiguous. In this case, each additional decamer is allowed to bear one base insertion or deletion between the median C and G. This set of criteria was validated by identifying within the promoter region of the IGF-BP3 gene the existence of a novel p53-responsive element whose functional significance was verified. By limiting our computer search to Vertebrate genes involved in cell cycle regulation, cellular adhesion or metastatic processes and to gene families most often found in HOVERGEN database, 7785 gene sequences were first analysed. Among the oncogenes, kinases, proteases and structural proteins, 55 new genes were selected; six of them were retrieved in more than one species.

ADP-ribosyl Cyclase↗
PubMed2005

Activated cyclic AMP-response element binding protein (CREB) is expressed in a myelin-associated protein in chick.

Cyclic AMP response element (CRE) is a specific DNA sequence, which mediates transcriptional activation in the response to the cyclic AMP-activated and protein kinase A dependent signaling pathway. In the present study, phosphorylated CRE binding protein (CREB) immunoreactivity was mainly localized in the white matter of chick central nervous system (CNS). We have further confirmed the specificity of phospho-CREB immunoreaction in myelin using demyelinated optic nerve induced by lysophophatidylcholine (LPC), which is known to produce demyelination with little axonal damage. Double immunofluorescent analyses with myelin basic protein (MBP) and transferrin binding protein (TfBP), oligodendrocyte marker showed that phospho-CREB recognized a myelin-related protein in chick. Immunoblot analyses showed that phospho-CREB recognized a protein with molecular weights of approximately 70 kDa. Our data suggest that the antigen recognized by phospho-CREB is a myelin-associated protein in the chick CNS.

Animals↗
PubMed2000

Regulation by homeoproteins: a comparison of deformed-responsive elements.

Homeotic genes of Drosophila melanogaster encode transcription factors that specify segment identity by activating the appropriate set of target genes required to produce segment-specific characteristics. Advances in understanding target gene selection have been hampered by the lack of genes known to be directly regulated by the HOM-C proteins. Here we present evidence that the gene 1.28 is likely to be a direct target of Deformed in the maxillary segment. We identified a 664-bp Deformed Response Element (1.28 DRE) that directs maxillary-specific expression of a reporter gene in transgenic embryos. The 1.28 DRE contains in vitro binding sites for Deformed and DEAF-1. The Deformed binding sites do not have the consensus sequence for cooperative binding with the cofactor Extradenticle, and we do not detect cooperative binding to these sites, though we cannot rule out an independent role for Extradenticle. Removing the four Deformed binding sites renders the 1.28 DRE inactive in vivo, demonstrating that these sites are necessary for activation of this enhancer element, and supporting the proposition that 1.28 is activated by Deformed. We show that the DEAF-1 binding region is not required for enhancer function. Comparisons of the 1.28 DRE with other known Deformed-responsive enhancers indicate that there are multiple ways to construct Deformed Response Elements.

Animals↗
PubMed2000

Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2.

A coordinated cellular response to oxidative stress occurs in part through transcriptional regulation via a cis-acting sequence known as the antioxidant response element (ARE). NF-E2-related factor 2 (Nrf2), a member of the Cap'n'Collar family of basic region-leucine zipper (bZIP) transcription factors, has been implicated as an essential component of an ARE-binding transcriptional complex, but the signaling pathway leading to its activation has remained unclear. Using a reporter gene assay, we found that ARE-directed transcription was activated by phorbol 12-myristate 13-acetate (PMA), but completely suppressed by staurosporine and Ro-32-0432, selective inhibitors of protein kinase C (PKC). Immunocytochemistry and subcellular fractionation revealed that PMA, like tert-butylhydroquinone (tBHQ), promoted the nuclear localization of Nrf2, a process that was blocked by staurosporine or Ro-32-0432. We showed that Nrf2, a previously unidentified kinase target, was phosphorylated in HepG2 cells. PMA transiently activated Nrf2 phosphorylation, whereas the addition of tBHQ or beta-naphthoflavone (betaNF) led to a persistent stimulation, which was abolished by staurosporine, but not by U0126 and SB203580, respective inhibitors of MEK and p38 kinases. Purified Nrf2 was phosphorylated in vitro by the catalytic subunit of PKC, or by PKC immunoprecipitated from cell lysates. Significantly, PKC precipitated from tBHQ- or betaNF-treated cells showed enhanced activity against Nrf2. These findings indicate an important role of the PKC pathway in the ARE-mediated gene expression, and suggest that PKC-directed phosphorylation of Nrf2 may be a critical event for the nuclear translocation of this transcription factor in response to oxidative stress.

Animals↗
PubMed2002

Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes.

Adaptation to hypoxia is a crucial process both physiologically (i.e. in chondrocytes) and pathologically (i.e. in tumor cells). Previous studies have shown that DEC1, a basic helix-loop-helix transcription factor, is induced by hypoxia in glioma cells (Ivanova, A. V., Ivanov, S. V., Danilkovitch-Miagkova, A., and Lerman, M. I. (2001) J. Biol. Chem. 276, 15306-15315). In the present study, we found that hypoxia or CoCl(2) enhanced the mRNA expression of DEC2, as well as DEC1, within 24 h in chondrogenic ATDC5, 293T, and HeLa cells. In luciferase assays, the regions between -524 and -401 in the DEC1 promoter, and between -863 and -258 in the DEC2 promoter, were responsible for the hypoxia- or hypoxia-inducible factor-1alpha (HIF-1alpha)-induced transcription. In these regions, we identified functional hypoxia response elements (HREs) that bound to HIF-1alpha and HIF-1beta. In addition to an HIF-1 binding site consensus sequence, the DEC1 HRE had cAMP response element-like and CACAG sequences, which were also involved in the transcription activation in response to HIF-1alpha. Although the DEC2 HRE did not have a cAMP response element-like or CACAG sequence, it showed a higher affinity for HIF-1 than did the DEC1 HRE. Because DEC1 and DEC2 are directly inducible by HIF-1, these transcription factors may be crucial for the adaptation to hypoxia.

Aryl Hydrocarbon Receptor Nuclear Translocator↗
PubMed2006

In vivo regulation of Grp78/BiP transcription in the embryonic heart: role of the endoplasmic reticulum stress response element and GATA-4.

The transcriptional activation of GRP78, which controls multiple signaling pathways of the unfolded protein response, has been used extensively as an indicator for the onset of endoplasmic reticulum stress in tissue culture systems. Here we investigate the mechanism of Grp78 induction during mouse embryonic development. Our results reveal that in transgenic mouse models, reporter gene activity driven by the Grp78 promoter is strongly activated during early embryonic heart development but subsides in later stages. This activation is strictly dependent on a 100-base pair region of the Grp78 promoter containing the endoplasmic reticulum stress response elements (ERSEs). Previous studies establish that endoplasmic reticulum stress induces in vivo binding of YY1 and the nuclear form of ATF6 to the ERSE. Since the expression of YY1 as well as ATF6 is ubiquitous in the mouse embryo, activation of the Grp78 promoter in the early embryonic heart may involve a specific mechanism. Here we report that GATA-4, a transcription factor essential for heart development, binds to the Grp78 promoter in vivo and activates the ERSE, which does not contain a consensus GATA binding site. GATA-4 cooperatively activates the Grp78 promoter with YY1, and the DNA binding domain of YY1 is necessary and sufficient for this cooperation. In addition, GATA-4 activation of the Grp78 promoter is enhanced by the nuclear form of ATF6, and this synergy is further potentiated by YY1. These results suggest that during early heart organogenesis, Grp78 can be activated through cooperation between the cell type-specific transcription factors and ERSE-binding factors.

Activating Transcription Factor 6↗
PubMed2001

Allosteric modulation of estrogen receptor conformation by different estrogen response elements.

Estrogen-regulated gene expression is dependent on interaction of the estrogen receptor (ER) with the estrogen response element (ERE). We assessed the ability of the ER to activate transcription of reporter plasmids containing either the consensus vitellogenin A2 ERE or the imperfect pS2, vitellogenin B1, or oxytocin (OT) ERE. The A2 ERE was the most potent activator of transcription. The OT ERE was significantly more effective in activating transcription than either the pS2 or B1 ERE. In deoxyribonuclease I (DNase I) footprinting experiments, MCF-7 proteins protected A2 and OT EREs more effectively than the pS2 and B1 EREs. Limited protease digestion of the A2, pS2, B1, or OT ERE-bound receptor with V8 protease or proteinase K produced distinct cleavage products demonstrating that individual ERE sequences induce specific changes in ER conformation. Receptor interaction domains of glucocorticoid receptor interacting protein 1 and steroid receptor coactivator 1 bound effectively to the A2, pS2, B1, and OT ERE-bound receptor and significantly stabilized the receptor-DNA interaction. Similar levels of the full-length p160 protein amplified in breast cancer 1 were recruited from HeLa nuclear extracts by the A2, pS2, B1, and OT ERE-bound receptors. In contrast, significantly less transcriptional intermediary factor 2 was recruited by the B1 ERE-bound receptor than by the A2 ERE-bound receptor. These studies suggest that allosteric modulation of ER conformation by individual ERE sequences influences the recruitment of specific coactivator proteins and leads to differential expression of genes containing divergent ERE sequences.

Allosteric Regulation↗
PubMed1998

p21(WAF1/CIP1) is upregulated by the geranylgeranyltransferase I inhibitor GGTI-298 through a transforming growth factor beta- and Sp1-responsive element: involvement of the small GTPase rhoA.

We have recently reported that the geranylgeranyltransferase I inhibitor GGTI-298 arrests human tumor cells at the G1 phase of the cell cycle and increases the protein and RNA levels of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1). Here, we show that GGTI-298 acts at the transcriptional level to induce p21(WAF1/CIP1) in a human pancreatic carcinoma cell line, Panc-1. This upregulation of p21(WAF1/CIP1) promoter was selective, since GGTI-298 inhibited serum responsive element- and E2F-mediated transcription. A functional analysis of the p21(WAF1/CIP1) promoter showed that a GC-rich region located between positions -83 and -74, which contains a transforming growth factor beta-responsive element and one Sp1-binding site, is sufficient for the upregulation of p21(WAF1/CIP1) promoter by GGTI-298. Electrophoretic mobility shift assays showed a small increase in the amount of DNA-bound Sp1-Sp3 complexes. Furthermore, the analysis of Sp1 transcriptional activity in GGTI-298-treated cells by using GAL4-Sp1 chimera or Sp1-chloramphenicol acetyltransferase reporter revealed a significant increase in Sp1-mediated transcription. Moreover, GGTI-298 treatment also resulted in increased Sp1 and Sp3 phosphorylation. These results suggest that GGTI-298-mediated upregulation of p21(WAF1/CIP1) involves both an increase in the amount of DNA-bound Sp1-Sp3 and enhancement of Sp1 transcriptional activity. To identify the geranylgeranylated protein(s) involved in p21(WAF1/CIP1) transcriptional activation, we analyzed the effects of the small GTPases Rac1 and RhoA on p21(WAF1/CIP1) promoter activity. The dominant negative mutant of RhoA, but not Rac1, was able to activate p21(WAF1/CIP1). In contrast, constitutively active RhoA repressed p21(WAF1/CIP1). Accordingly, the ADP-ribosyl transferase C3, which specifically inhibits Rho proteins, enhanced the activity of p21(WAF1/CIP1). Taken together, these results suggest that one mechanism by which GGTI-298 upregulates p21(WAF1/CIP1) transcription is by preventing the small GTPase RhoA from repressing p21(WAF1/CIP1) induction.

Alkyl and Aryl Transferases↗
PubMed2004

Targeting estrogen responsive elements (EREs): design of potent transactivators for ERE-containing genes.

The estrogen hormone (E2) plays an important role in the physiology and pathophysiology of target tissues. The effects of E2 are conveyed by the estrogen receptors (ER) alpha and beta. The E2-ER complex mediates an array of genomic and non-genomic events that orchestrate the expression of a number of genes involved in the regulation of cell proliferation and differentiation. The interaction of with the regulatory DNA sequence, estrogen responsive element (ERE), of each responsive gene constitutes a critical genomic signaling pathway. However, the relative importance of ERE-dependent E2-ER signaling in cell proliferation remains to be elucidated. To address this issue, we engineered ERE-binding activators (EBAs) that specifically and potently regulate ERE-containing genes. The modular nature of ER allowed us to initially design a monomeric ERE-binding module by genetically joining two DNA-binding domains with the hinge domain. Integration of strong activation domains from other transcription factors into this module generated constitutively active EBAs. These transactivators robustly induced the expression of only ERE-containing promoter constructs in transfected cells independent of ligand, dimerization, ER-subtype and -status. Moreover, EBAs altered cell cycle progression in breast cancer cell lines in a manner similar to E2-ER. These results demonstrate the importance of ERE-containing genes in the regulation of cell proliferation. These novel ERE-binding transregulators could also be a basis for the targeted regulation of ERE-containing genes, the identification of estrogen responsive gene networks, and the development of alternative/complementary therapeutic approaches for estrogen target tissue cancers.

Animals↗
PubMed2000

A SAF binding site in the promoter region of human gamma-fibrinogen gene functions as an IL-6 response element.

Expression of fibrinogen is highly induced during inflammation, and such abnormal expression of this protein is considered as a major cardiovascular risk factor. IL-6 is one of the main mediators of abnormal expression of fibrinogen leading to the pathogenic conditions. Transient transfection and EMSA were performed to investigate the molecular mechanism of IL-6-induced gamma-fibrinogen gene expression in hepatic cells. Using progressively deleted 5' fragments of the gamma-fibrinogen promoter coupled to chloramphenicol acetyltransferase gene, an IL-6 responsive element located between positions -273 and -259 was identified. Mutation of this element abrogates IL-6 responsiveness of the gamma-fibrinogen promoter. Interaction of this promoter with a zinc finger transcription factor, serum amyloid A activating factor (SAF)-1, was demonstrated by EMSA. Furthermore, overexpression of wild-type SAF-1 in transfected liver cells can increase transcription of the gamma-fibrinogen promoter. These data show that transcription factor SAF-1 is involved in the regulation of IL-6-mediated induction of the human gamma-fibrinogen gene in liver cells.

Binding Sites↗
PubMed1994

Multiple prolactin-responsive elements mediate G1 and S phase expression of the interferon regulatory factor-1 gene.

The interferon regulatory factor-1 (IRF-1) gene is both an immediate-early G1 phase gene and an S phase gene inducible by PRL in rat Nb2 T lymphocytes. To understand the mechanism by which PRL regulates the biphasic expression of IRF-1, we cloned the rat IRF-1 gene and functionally characterized the IRF-1 promoter. Upon transfection into Nb2 T cells, 1.7 kilobases (kb) of IRF-1 5'-flanking DNA linked to a chloramphenicol acetyl transferase (CAT) reporter gene mediated a 30-fold induction of CAT enzyme activity in response to 24 h of PRL stimulation. Deletion mutants containing 1.3, 0.6, and 0.2 kb 5'-flanking DNA were incrementally less transcriptionally active, although 0.2 kb still mediated a 12-fold induction by PRL. The sequence between -1.7 and -0.2 kb linked to a heterologous thymidine kinase promoter failed to respond to PRL stimulation, suggesting that the activity of upstream PRL response elements may require an interaction with promoter-proximal elements. By assaying CAT enzyme activity across a 24-h PRL induction time course, we were able to assign G1 vs. S phase PRL responses of the IRF-1 gene to different regions of the IRF-1 5'-flanking and promoter DNA. The 0.2-kb IRF-CAT construct was induced by PRL stimulation during the G1 phase of the cell cycle. In contrast, the 1.7-kb IRF-CAT construct was inducible by PRL during both G1 and S phase of the cell cycle. Hence, the PRL-induced biphasic expression of the IRF-1 gene appears to be controlled by separate PRL-responsive elements: elements in the first 0.2 kb of the IRF-1 promoter region act during early activation, and elements between 0.2 and 1.7 kb act in concert with the proximal 0.2-kb region during S phase progression.

Animals↗
PubMed2001

Cyclic AMP response element binding protein (CREB) and CREB binding protein (CBP) in global cerebral ischemia.

Cyclic AMP (cAMP) response element binding protein (CREB) is a transcription factor that has been implicated in neuronal responses to ischemia. We examined the effect of global cerebral ischemia in the rat on the expression of CREB, its transcriptionally active phosphorylated form (pCREB), and the nuclear adaptor protein, CREB binding protein (CBP). Global ischemia induced the expression of pCREB and CBP in vulnerable neurons of the hippocampal CA1 sector. In primary cultures of murine cortical neurons subjected to hypoxia, CBP was selectively expressed in cells with morphologically intact cell nuclei, and not in cells with condensed or fragmented nuclei indicative of irreversibly damaged neurons. These results support a role for transcriptional activation by CREB and CBP in neuronal cell-survival programs following cerebral ischemia.

Animals↗
PubMed2004

Matrix metalloproteinase 9 expression is coordinately modulated by the KRE-M9 and 12-O-tetradecanoyl-phorbol-13-acetate responsive elements.

To investigate the pathophysiologic role of matrix metalloproteinase 9 (MMP-9), we analyzed the mechanism of its transcriptional regulation in keratinocytes and in HT1080 fibrosarcoma cells in culture. The KRE-M9 element, which is located between the 12-O-tetradecanoyl-phorbol-13-acetate responsive element (TRE) and the transcription initiation site in the MMP-9 promoter, is essential for MMP-9 transcription in the absence of the TRE. The KRE-M9 binding protein, however, is shown to be a repressor of transcription rather than an activator; we found several times higher transcriptional activity when the KRE-M9 element was mutated. In contrast, activator protein 1 proteins (AP-1) are shown to activate transcription of MMP-9 by binding to the TRE, which is located adjacent to the KRE-M9 element. Moreover, we found that the KRE-M9 binding protein could serve as a differentiation repressing factor 1 (DRF-1) as shown by the decrease in levels of this protein with differentiation. In addition, the TRE binding protein is able to bind to the KRE-M9 to some extent. These results indicate that the coordinated modulation of MMP-9 transcription via the TRE and the KRE-M9 elements is important in epidermal and mesenchymal tissues. Our findings could facilitate consideration of the molecular mechanism in a variety of pathophysiologic conditions with which MMP-9 is involved.

Carcinogens↗