Biomedical subjects

J A Hassell

Publications and source records attributed to J A Hassell.

At least 19 recordsLinked to original sources

PubMed2001

The pea3 subfamily ets genes are required for HER2/Neu-mediated mammary oncogenesis.

BACKGROUND: The PEA3 Ets transcription factor is overexpressed in the vast majority of human breast tumors and in nearly all of those of the HER2/Neu-positive subclass. PEA3 is also overexpressed in various transgenic mouse models of this disease. Whether PEA3 plays an essential role in HER2/Neu-mediated oncogenesis has heretofore not been addressed. RESULTS: Here, we report that each of the three highly related ets genes of the pea3 subfamily (pea3, er81, and erm) were coordinately overexpressed in mammary tumors of MMTV-neu transgenic mice. Other ets genes normally expressed in the mammary gland were not upregulated in these tumors. Expression of a dominant-negative pea3 transgene under the control of the MMTV promoter in mammary epithelial cells of MMTV-neu transgenic mice dramatically delayed the onset of mammary tumors and reduced the number and size of such tumors in individual mice. Those tumors that arose in bitransgenic mice expressed the MMTV-neu transgene, but not the MMTV-dominant-negative pea3 transgene. CONCLUSIONS: These findings imply that one or more of the PEA3 subfamily Ets proteins or other Ets proteins with related DNA binding specificity play an essential role in Neu-mediated mammary oncogenesis. Hence, agents that inhibit the expression or activity of the PEA3 subfamily proteins may prove efficacious in the treatment of breast cancer.

Animals↗

PubMed2001

PEA3 is up-regulated in response to Wnt1 and activates the expression of cyclooxygenase-2.

The inducible prostaglandin synthase cyclooxygenase-2 (COX-2) is aberrantly expressed in intestinal tumors resulting from APC mutation, and is also transcriptionally up-regulated in mouse mammary epithelial cells in response to Wnt1 expression. beta-Catenin stabilization is a consequence of both APC mutation and Wnt signaling. We have previously observed coordinate regulation of the matrilysin promoter by beta-catenin and Ets family transcription factors of the PEA3 subfamily. Here we show that while beta-catenin only weakly activates the COX-2 promoter, PEA3 family transcription factors are potent activators of COX-2 transcription. Consistent with this, PEA3 is up-regulated in Wnt1-expressing mouse mammary epithelial cells, and PEA3 factors are highly expressed in tumors from Wnt1 transgenic mice, in which Cox-2 is also up-regulated. Promoter mapping experiments suggest that the NF-IL6 site in the COX-2 promoter is important for mediating PEA3 responsiveness. The NF-IL6 site is also important for COX-2 transcription in some colorectal cancer lines (Shao, J., Sheng, H., Inoue, H., Morrow, J. D., and DuBois, R. N. (2000) J. Biol. Chem. 275, 33951-33956), and PEA3 factors are highly expressed in colorectal cancer cell lines. Therefore, we speculate that PEA3 factors may contribute to the up-regulation of COX-2 expression resulting from both APC mutation and Wnt1 expression.

Animals↗

PubMed2001

Role of Ets transcription factors in mammary gland development and oncogenesis.

PEA3 is the founding member of a subfamily of closely related ets genes that includes ER81 and ERM. PEA3 is expressed in the epithelial cells of mammary buds at the time that these first appear during mouse embryogenesis, and it is differentially expressed during postnatal mammary gland development. PEA3 expression is highest at the onset of puberty and during early pregnancy, times of extensive epithelial outgrowth and branching. PEA3 is expressed in undifferentiated epithelial cap cells of terminal end buds, and in differentiated myoepithelial cells of ducts and alveoli. Loss-of-function mutations in the PEA3 gene compromise mammary ductal branching at the onset of puberty and early during pregnancy. PEA3 is overexpressed in the vast majority of human breast tumors and in nearly all of the HER2-positive subclass of such tumors. PEA3 is similarly overexpressed in transgenic mouse models of this malignancy. Expression of dominant-negative PEA3 in the mouse mammary gland of MMTV-HER2 transgenic mice dramatically delays the onset and reduces the incidence of mammary tumors. Hence PEA3 and/or its close relatives play key regulatory roles in both mammary gland development and oncogenesis.

Animals↗

PubMed2001

The PEA3 subfamily of Ets transcription factors synergizes with beta-catenin-LEF-1 to activate matrilysin transcription in intestinal tumors.

The matrix metalloproteinase matrilysin (MMP-7) is expressed in the tumor cells of a majority of mouse intestinal and human colonic adenomas. We showed previously that matrilysin is a target gene of beta-catenin-Tcf, the transcription factor complex whose activity is thought to play a crucial role in the initiation of intestinal tumorigenesis. Here we report that overexpression of a stable mutant form of beta-catenin alone was not sufficient to effect expression of luciferase from a matrilysin promoter-luciferase reporter plasmid. However, cotransfection of the reporter with an expression vector encoding the PEA3 Ets transcription factor, or its close relatives ER81 and ERM, increased luciferase expression and rendered the promoter responsive to beta-catenin-LEF-1 as well as to the AP-1 protein c-Jun. Other Ets proteins could not substitute for the PEA3 subfamily. Luciferase activity was induced up to 250-fold when PEA3, c-Jun, beta-catenin, and LEF-1 were coexpressed. This combination of transcription factors was also sufficient to induce expression of the endogenous matrilysin gene. Furthermore, all matrilysin-expressing benign intestinal tumors of the Min mouse expressed a member of the PEA3 subfamily, as did all human colon tumor cell lines examined. These data suggest that the expression of members of the PEA3 subfamily, in conjunction with the accumulation of beta-catenin in these tumors, leads to coordinate upregulation of matrilysin gene transcription, contributing to gastrointestinal tumorigenesis.

Animals↗

PubMed2000

The PEA3 Ets transcription factor comprises multiple domains that regulate transactivation and DNA binding.

PEA3, a member of the Ets family of transcription factors, is a nuclear phosphoprotein capable of activating transcription. Mouse PEA3 comprises 480 amino acids and bears an approximately 85-amino acid ETS domain near its carboxyl terminus. Whereas analyses of bacterially expressed PEA3 revealed that the ETS domain is required for sequence-specific DNA binding, little is known of the functional domains in the protein required for its activity in mammalian cells. To this end, we defined the location of the PEA3 functional domains in COS cells. PEA3 bears a strong activation domain near its amino terminus, which is flanked by two regions that independently negatively regulate its activity. PEA3 expressed in COS cells was incapable of binding to DNA in vitro. However, DNA binding activity could be unmasked by incubation with a PEA3-specific antibody. Analyses of the DNA binding activity of PEA3 deletion mutants revealed that two regions flanking the ETS domain independently inhibited DNA binding; deletion of both regions was required to detect DNA binding in the absence of a PEA3-specific antibody. Under these conditions, the ETS domain was sufficient for sequence-specific DNA binding. These findings suggest that the activity of PEA3 is exquisitely controlled at multiple functional levels.

Animals↗

PubMed2000

Male sexual dysfunction in mice bearing targeted mutant alleles of the PEA3 ets gene.

PEA3, a member of the Ets family of transcriptional regulatory proteins, is expressed in a unique spatial and temporal pattern during mouse embryogenesis; its overexpression is positively correlated with HER2-mediated breast tumorigenesis in both humans and mice. To determine whether PEA3 plays a part in development and oncogenesis and to uncover its normal physiological role, we generated mice lacking functional PEA3 by gene targeting in embryonic stem cells. PEA3(-/-) mice arose from heterozygous crosses with the expected Mendelian frequency, revealing that PEA3 is dispensable for embryogenesis. PEA3 mutant mice displayed no overt phenotype and lived a normal life span. However, PEA3-deficient males failed to reproduce. PEA3 is expressed in several male sexual organs, but gross and histological analyses of the organs from PEA3(-/-) mice revealed no abnormalities. Spermatogenesis and spermiogenesis also appeared normal in mice homozygous for the PEA3 mutation, and their sperm were capable of fertilizing eggs in vitro. PEA3(-/-) males engaged in normal mating behavior, but they did not set copulatory plugs and sperm could not be detected in the uteri of females that had mated with PEA3(-/-) males. Erections could be evoked by abdominal pressure in PEA3-deficient male mice, and the results of in vitro experiments revealed that the corpus cavernosum isolated from PEA3 mutant males relaxed in response to acetylcholine. Therefore, the infertility of PEA3 mutant males involves either mechanisms proximal to the cavernosal smooth muscle or an ejaculatory dysfunction. However, PEA3 mutant mice are phenotypically distinguishable from other knockout mice with such deficits and thus provide a unique model for further investigation of male sexual dysfunction.

Acetylcholine↗

PubMed1998

The PEA3 Ets transcription factor is a downstream target of the HER2/Neu receptor tyrosine kinase.

The HER2/neu gene, which is overexpressed in 20-30% of human breast tumors, encodes a receptor tyrosine kinase that functions through multiple signaling pathways to regulate the activity of nuclear transcription factors. We have reported that PEA3, an Ets family transcription factor, is overexpressed in HER2/Neu-induced breast tumors and their metastases. To account for the increased levels of PEA3 in these tumors we have suggested that HER2/Neu enhances PEA3 transcriptional activity, which then acts to stimulate expression of the PEA3 gene. This hypothesis is consistent with the occurrence of PEA3 binding sites in the PEA3 promoter and with the ability of PEA3 to transactivate this promoter. To learn whether HER2/Neu indeed regulates PEA3 activity we measured the capacity of constitutively-activated HER2/Neu to affect PEA3-dependent reporter gene expression. Coexpression of PEA3 and HER2/Neu stimulated PEA3-dependent reporter gene expression to a much greater extent than did either protein alone suggesting that HER2/Neu upregulates the transcriptional activity of PEA3. To define the pathway whereby HER2/Neu functions we employed dominant-negative mutants of signaling proteins known to be downstream of HER2/Neu. Overexpression of Rap1a, a Ras-related protein capable of antagonizing Ras function, completely inhibited the ability of HER2/Neu to stimulate PEA3-dependent gene expression. Ras is known to stimulate at least two mitogen-activated protein kinase (MAPK) cascades, the extracellular-regulated kinase (ERK) cascade and the stress-activated kinase (SAPK) or Jun kinase (JNK) cascade. Similarly, HER2/Neu activated both ERKs and SAPKs/JNKs in a Ras-dependent fashion. Dominant-inhibitory mutants in either the ERK or SAPK/JNK cascades partially inhibited HER2/Neu activation of PEA3-dependent gene expression. These findings suggest that HER2/Neu regulates PEA3 activity through two different Ras-dependent MAPK pathways.

Animals↗

PubMed1998

Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis.

Transgenic mice expressing the polyomavirus (PyV) middle T antigen (MT) develop multifocal mammary tumors which frequently metastasize to the lung. The potent transforming activity of PyV MT is correlated with its capacity to activate and associate with a number of signaling molecules, including the Src family tyrosine kinases, the 85-kDa Src homology 2 subunit of the phosphatidylinositol 3' (PI-3') kinase, and the Shc adapter protein. To uncover the role of these signaling proteins in MT-mediated mammary tumorigenesis, we have generated transgenic mice that express mutant PyV MT antigens decoupled from either the Shc or the PI-3' kinase signaling pathway. In contrast to the rapid induction of metastatic mammary tumors observed in the strains expressing wild-type PyV MT, mammary epithelial cell-specific expression of either mutant PyV MT resulted in the induction of extensive mammary epithelial hyperplasias. The mammary epithelial hyperplasias expressing the mutant PyV MT defective in recruiting the PI-3' kinase were highly apoptotic, suggesting that recruitment of PI-3' kinase by MT affects cell survival. Whereas the initial phenotypes observed in both strains were global mammary epithelial hyperplasias, focal mammary tumors eventually arose in all female transgenic mice. Genetic and biochemical analyses of tumorigenesis in the transgenic strains expressing the PyV MT mutant lacking the Shc binding site revealed that a proportion of the metastatic tumors arising in these mice displayed evidence of reversion of the mutant Shc binding site. In contrast, no evidence of reversion of the PI-3' kinase binding site was noted in tumors derived from the strains expressing the PI-3' kinase binding site MT mutant. Tumor progression in both mutant strains was further correlated with upregulation of the epidermal growth factor receptor family members which are known to couple to the PI-3' kinase and Shc signaling pathways. Taken together, these observations suggest that PyV MT-mediated tumorigenesis requires activation of both Shc and PI-3' kinase, which appear to be required for stimulation of cell proliferation and survival signaling pathways, respectively.

Adaptor Proteins, Signal Transducing↗

PubMed1997

HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer.

HER2/Neu is overexpressed in 25-30% of all human breast cancers as a result of both gene amplification and enhanced transcription. Transcriptional upregulation of HER2/neu leads to a 6-8-fold increased abundance of its mRNA per gene copy and likely results from the elevated activity of transcription factors acting on the HER2/neu promoter. Here we report that transcripts of PEA3, an ETS transcription factor implicated in oncogenesis, were increased in 93% of HER2/Neu-overexpressing human breast tumor samples. Analyses to uncover the molecular basis for elevated PEA3 transcripts in HER2/Neu-positive breast tumors revealed that the HER2/Neu receptor tyrosine kinase initiated an intracellular signaling cascade resulting in increased PEA3 transcriptional activity; transcriptionally-activated PEA3 stimulated HER2/neu and PEA3 gene transcription by binding to sites in the promoters of these genes. PEA3 also activates transcription of genes encoding matrix-degrading proteinases, enzymes required for tumor cell migration and invasion. These findings implicate PEA3 in the initiation and progression of HER2/Neu positive breast cancer, and suggest that PEA3 and signaling proteins affecting its regulation are appropriate therapeutic targets.

Animals↗

PubMed1997

Polyomavirus large T-antigen binds the "pRb related' protein p130 through sequences in conserved region 2.

The transforming potential of DNA tumor viruses derives mainly from the ability of their encoded oncogene products to interact with cellular proteins. Many of these viral oncoproteins share regions of sequence similarity, designated conserved region 1 and 2, which have been implicated in complex formation with pRb, the product of the retinoblastoma tumor suppressor gene, and related p107 and p130 species. It has now been shown that the EIA protein of adenovirus is able to bind to all three pRb-related proteins through sequences in conserved region 1 and 2. We have shown previously that polyomavirus large T-antigen also interacts with pRb and p107 in vitro. The pRb and p107 binding domains reside between residues 141, 158 which include conserved region 2. In the present study, we demonstrate that polyomavirus large T-antigen also interacted with p130 in vitro through the same sequences in conserved region 2.

Amino Acid Sequence↗

PubMed1997

A role for the ETS domain transcription factor PEA3 in myogenic differentiation.

Activation of adult myoblasts called satellite cells during muscle degeneration is an important aspect of muscle regeneration. Satellite cells are believed to be the only myogenic stem cells in adult skeletal muscle and the source of regenerating muscle fibers. Upon activation, satellite cells proliferate, migrate to the site of degeneration, and become competent to fuse and differentiate. We show here that the transcription factor polyomavirus enhancer activator 3 (PEA3) is expressed in adult myoblasts in vitro when they are proliferative and during the early stages of differentiation. Overexpression of PEA3 accelerates differentiation, whereas blocking of PEA3 function delays myoblast fusion. PEA3 activates gene expression following binding to the ets motif most efficiently in conjunction with the transcription factor myocyte enhancer factor 2 (MEF2). In vivo, PEA3 is expressed in satellite cells only after muscle degeneration. Taken together, these results suggest that PEA3 is an important regulator of activated satellite cell function.

Animals↗

PubMed1996

The activity of the Ets transcription factor PEA3 is regulated by two distinct MAPK cascades.

PEA3, a member of the Ets family of transcriptional regulatory proteins, binds to the PEA3 promoter element and stimulates transcription through this site. The activity of the PEA3 element is regulated by mitogens, activated receptor tyrosine kinases, and oncogenic members of the Ras signal transduction pathway. However, it is not clear whether PEA3 mediates transcriptional regulation by these agents because a number of different Ets proteins can functionally interact with the PEA3 element. To specifically learn whether the activity of PEA3 is regulated, we investigated the ability of constitutively-activated Ras (Ha-RasV12) and signaling proteins downstream of Ras to alter PEA3-dependent reporter gene expression in COS cells. Ha-RasV12 and activated proteins in both the extra-cellular regulated kinase (ERK) and the stress-activated protein kinase (SAPK) or Jun N-terminal kinase (JNK) cascades independently stimulated PEA3-mediated gene expression. Ha-RasV12 stimulation of PEA3 activity was reduced by dominant-negative mutants in each of these protein kinase cascades, suggesting that Ras activates PEA3 through both pathways. Furthermore, the ability of unique activators of each kinase cascade to stimulate PEA3-dependent gene expression was selectively reduced by dominant-negative mutants within the homologous but not the heterologous pathway. Hence two distinct mitogen-activated protein kinase (MAPK) cascades regulate PEA3 activity. PEA3 was phosphorylated in vivo at serine residues consistent with the possibility that it may be a direct target of MAPKs.

Animals↗

PubMed1996

Functional implications of mutations within polyomavirus large T antigen Rb-binding domain: effects on pRb and p107 binding in vitro and immortalization activity in vivo.

In this study, we have extensively modified the Rb-binding domain of polyomavirus large T antigen. Mutant polyomavirus large T antigens were tested for their ability to bind pRb and p107 in vitro and assayed for their capacity to immortalize primary rat embryo fibroblasts in vivo. Polyomavirus large T antigen bound pRb and p107 through a common region located between amino acids 141 to 158, containing the consensus Rb-binding sequence D/N-L-X-C-X-E. Substitution of any amino acid within the core Rb-binding sequence abolished pRb and p107 binding in vitro and immortalization activity in vivo. Substitution of amino acids outside the core Rb-binding sequence reduced pRb and p107 binding in vitro and decreased or abolished immortalization of rat embryo fibroblasts in vivo. Although duplication of the Rb-binding domain within the polyomavirus large T antigen results in a molecule that can bind at least twice as much pRb and p107 in vitro, this mutant displayed an essentially wild-type level of immortalization activity. More importantly, we found that the addition of acidic residues within the casein kinase II consensus phosphorylation region flanking the Rb-binding domain, or the deletion of amino acids 256 to 272, increased the immortalizing activity of the mutant polyomavirus large T antigen. These two mutants displayed a greater than wild-type level of pRb binding in vitro, while in contrast, a decreased affinity for p107 binding in vitro was observed. Together, these results indicate that while pRb binding appears to be an essential event for immortalization, there is no tight correlation between the frequency of immortalization and the absolute level of pRb binding in vitro, indicating that other large T antigen functions are important for cellular immortalization.

Amino Acid Sequence↗

PubMed1995

The cDNA sequence of human endothelial cell multimerin. A unique protein with RGDS, coiled-coil, and epidermal growth factor-like domains and a carboxyl terminus similar to the globular domain of complement C1q and collagens type VIII and X.

Multimerin is a massive, soluble protein found in platelets and in the endothelium of blood vessels. Multimerin is composed of varying sized, disulfide-linked multimers, the smallest of which is a homotrimer. Multimerin is a factor V/Va-binding protein and may function as a carrier protein for platelet factor V. The cDNA for human multimerin was isolated from lambda gt11 endothelial cell libraries using antibodies, and the isolated cDNA clones were used to obtain the full sequence. The full-length multimerin cDNA was 4.2 kilobase pairs. Northern analyses identified a 4.7-kilobase transcript in cultured endothelial cells, a megakaryocytic cell line, platelets, and highly vascular tissues. The multimerin cDNA can encode a protein of 1228 amino acids with the probable signal peptide cleavage site between amino acids 19 and 20. The protein is predicted to be hydrophilic and to contain 23 N-glycosylation sites. The adhesive motif RGDS (Arg-Gly-Asp-Ser) and an epidermal growth factor-like domain were identified. Sequence searches indicated that multimerin is a unique protein. Analyses identified probable coiled-coil structures in the central portion of the multimerin sequence. Additionally, the carboxyl-terminal region of multimerin resembles the globular, non-collagen-like, carboxyl-terminal domains of several other trimeric proteins, including complement C1q and collagens type VIII and X.

Amino Acid Sequence↗

PubMed1995

A transgenic mouse line harboring a smooth muscle alpha-actin promoter polyomavirus middle T antigen transgene develops an epithelial hyperplasia in the rectum and distal stomach.

BACKGROUND: Transgenic mice are the product of the microinjection of foreign DNA directly into the pronuclei of a one-cell embryo. The foreign DNA can cause insertional inactivation or activation of the flanking genetic locus. EXPERIMENTAL DESIGN: We isolated five lines of transgenic mice harboring the chicken alpha-actin vascular smooth muscle enhancer/promoter linked to the polyomavirus middle T antigen using a standard microinjection protocol. The expression of the transgene was assessed in RNA prepared from affected and nonaffected tissue by RNase protection and reverse transcriptase-polymerase chain reaction analyses. Cell morphology was determined in stained sections from fixed tissues. RESULTS: In this article, we document the development of epithelial hyperplasia in the rectum and distal stomach together with female infertility in a single line of transgenic mice harboring the transgene. We were unable to demonstrate the expression of the transgene in any tissue examined, regardless of the degree of hyperplasia. The phenotype was present in the heterozygous state in both males and females. CONCLUSIONS: In the absence of the expression of the transgene, we conclude that the insertion of the transgene may have caused the epithelial hyperplasia directly or may have contributed to a condition that promotes hyperplasia. The transgene may have activated a dominant-acting neighboring gene.

Actins↗

PubMed1993

The transactivator proteins VP16 and GAL4 bind replication factor A.

Many transcription factors can activate the initiation of DNA replication. We have used affinity chromatography to show that the acidic activation domains of the transcription factors VP16, GAL4, and p53 each bind selectively to human and yeast replication factor A (RPA). The binding is direct and to the largest subunit of the trimeric RPA complex, RPA-1. Mutations in VP16 that reduce the ability of GAL4-VP16 to activate polyomavirus DNA replication also compromise the binding of VP16 to RPA. We suggest that transcription factors may interact with RPA either to stabilize single-stranded DNA at a replication origin or to recruit DNA polymerase alpha to the replication initiation complex.

DNA-Binding Proteins↗

PubMed1993

PEA3 is overexpressed in mouse metastatic mammary adenocarcinomas.

Transgenic mice bearing the rat neu proto-oncogene under the transcriptional control of the mouse mammary tumor virus (MMTV) promoter develop focal mammary adenocarcinomas after long latency that are metastatic to the lung in a high percentage of the tumor-bearing animals. Because expression of the neu gene in the mammary epithelium precedes the occurrence of tumors, it appears that another genetic event in addition to neu transgene expression is required for tumorigenesis. We have investigated the expression of PEA3, a new member of the ets oncogene family of transcriptional regulatory factors, in neu-induced mammary tumors to learn whether PEA3 plays a role in tumor progression in this organ. We observed high levels of PEA3 RNA in neu-induced tumors, but little, if any, PEA3 RNA in the surrounding mammary epithelium. Moreover, mammary tumors that had metastasized to the lung also overexpressed the PEA3 gene, whereas normal lung tissue did not. Similar results were obtained after analyses of other transgenic mouse lines bearing metastatic mammary tumors induced by polyomavirus middle T antigen. These findings suggest that enhanced expression of PEA3 may be required to facilitate mammary tumor progression and metastasis.

Adenocarcinoma↗

PubMed1992

Involvement of AP1 and PEA3 binding sites in the regulation of murine tissue inhibitor of metalloproteinases-1 (TIMP-1) transcription.

Transcription of tissue inhibitor of metalloproteinases-1 (TIMP-1), a secreted protein that regulates the activities of the metalloproteinases, collagenase and stromelysin, is activated by serum growth factors. Transient transfection experiments have revealed several regions of cis-acting regulatory sequences involved in the response of the murine TIMP-1 gene to serum. One area is in the vicinity of the promoter, consisting of a non-consensus binding site (5'-TGAGTAA-3' at -59/-53) for transcription factor AP1 and an adjacent 24 bp region of dyad symmetry that contains a PEA3-binding site. A second is an upstream region (-1020 to -780) that acts as an enhancer when linked to a heterologous promoter, and contains a consensus AP1 binding site (at -803/ -797). Gel retardation assays revealed differences between nuclear factors in mouse C3H10T1/2 cells that bound to the TIMP(-59/ -53)AP1 site and a consensus collagenase TRE (TPA-response element). The TIMP(-59/ -53)AP1 site is a promiscuous motif that binds c-Fos/c-Jun AP1 translated in vitro and is an effective competitor for binding of nuclear AP1 factors to the consensus TRE, but in addition it binds factors that do not associate with the consensus TRE. The TIMP(-59/ -53)AP1 motif and the dyad symmetry region stimulated expression from a thymidine kinase promoter in an additive fashion, and competition experiments showed that excess copies of these factor binding sites reduced expression from a reporter plasmid driven by the TIMP-1 promoter. Our data show that binding sites for AP1 and PEA3 transcription factors are involved in the regulation of TIMP-1 transcription, which suggests that the coordinated induction of TIMP-1, collagenase and stromelysin may be achieved through the actions of a shared set of nuclear transcription factors. However, the properties of the TIMP-1(-59/ -53)AP1 motif likely reflect an additional type of transcriptional regulation restricted to TIMP-1.

Animals↗