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PubMed1997

Drosophila Jun relays the Jun amino-terminal kinase signal transduction pathway to the Decapentaplegic signal transduction pathway in regulating epithelial cell sheet movement.

We have characterized mutations in the Drosophila homolog of the mammalian proto-oncogene c-Jun gene (Djun). We demonstrate that DJUN in the embryo is a downstream target of the JNK signal transduction pathway during dorsal closure formation, and that the function of the JNK/DJUN pathway is to control the localized expression of decapentalegic (dpp), a member of the TGF-beta growth factor family. In contrast to previous observations, we find that both in the embryo and during photoreceptor cell determination, DJUN is not regulated by a pathway that involves MAPK.

Animals↗

PubMed1993

Functional divergence of protein kinase C (PKC) family members. PKC gamma differs from PKC alpha and -beta II and nPKC epsilon in its competence to mediate-12-O-tetradecanoyl phorbol 13-acetate (TPA)-responsive transcriptional activation through a TPA-response element.

We have established an assay system where overexpression of a specific protein kinase C (PKC) type caused by introduction of the respective cDNA results in the enhancement of a cell response: the transcriptional activation of a set of genes in response to PKC activators such as 12-O-tetradecanoylphorbol 13-acetate (TPA). When monitored by the expression of a reporter gene containing the chloramphenicol acetyltransferase gene fused downstream of a synthetic TPA response element (TRE) or a serum response element (SRE), the overexpression of cPKC alpha and -beta II or nPKC epsilon all resulted in the enhancement of transcriptional activation through both TRE and SRE. On the other hand, PKC gamma activates TRE only very weakly, although it activates SRE in a similar manner to the other PKC members examined. The overexpression of cPKC alpha and -beta II or nPKC epsilon, but not cPKC gamma, resulted in the enhanced expression of the endogenous c-jun gene, which contains TRE in the 5'-upstream, promoter region. The gel mobility shift assay showed that the activation of PKC gamma, as well as PKC alpha and -beta II and nPKC epsilon, causes the increase in TRE-binding proteins, suggesting that transcriptional activation through TRE requires an additional step, which is not activated by PKC gamma, such as a qualitative change in TRE-binding or in TRE-associating proteins. This finding provides not only a rationale to explain the presence of multiple PKC family members, but also permits the dissection of the complex cellular signaling cascade involving PKC family members.

Amino Acid Sequence↗

PubMed1990

Transcriptional regulation of the transforming growth factor beta 1 promoter by v-src gene products is mediated through the AP-1 complex.

Growth factor-independent 32D-src and 32D-abl cell lines, established by infecting the interleukin-3-dependent myeloid precursor cell line (32D-123) with retroviruses containing the src or abl oncogene, were used to study transcriptional regulation of transforming growth factor beta 1 (TGF-beta 1) mRNA. Analysis of different TGF-beta 1 promoter constructs regulated by pp60v-src indicated that sequences responsive to high levels of src induction contain binding sites for AP-1. Both src and serum induced expression of the c-fos and c-jun genes in myeloid cells, resulting in transcriptional activation of the TGF-beta 1 gene. We found that serum treatment increased TGF-beta 1 mRNA levels in 32D-123 cells and that the v-Src protein could replace the serum requirement by stimulating binding to the AP-1 complex of the TGF-beta 1 promoter, thereby mediating the induction of TGF-beta 1 transcription.

Animals↗

PubMed2001

Vascular smooth muscle cell activation and growth by 4-hydroxynonenal.

The present study examines the signal transduction mechanism that is involved in the growth of vascular smooth muscle cells exposed to 4-hydroxynonenal (HNE) in vitro. This aldehyde component of oxidized low-density lipoprotein has been identified in atherosclerotic lesion. Exposure to HNE caused ERK, JNK, and p38 MAP kinase activation as well as the induction of c-fos and c-jun gene expression. AP-1 activity was also significantly induced by HNE treatment. These intracellular activities appear to be the mechanism of HNE-caused mitogenesis. Indeed, HNE induced vascular smooth muscle cell proliferation as determened by Alamar-Blue assay and stimulated DNA synthesis as determined by bromodeoxyuridine incorporation. These observations are consistent with a role of lipid peroxidation products in vascular smooth muscle cell growth in atherogenesis.

Aldehydes↗

PubMed2000

Role of c-jun expression increased by heat shock- and ceramide-activated caspase-3 in HL-60 cell apoptosis. Possible involvement of ceramide in heat shock-induced apoptosis.

Ceramide has emerged as a lipid mediator in apoptosis induced by a variety of stresses. As we previously showed that the activation of AP-1, a nuclear transcription factor was indispensable to ceramide-induced apoptosis in human leukemia HL-60 cells (Sawai, H., Okazaki, T., Yamamoto, H., Okano, H., Takeda, Y., Tashima, M., Sawada, H., Okuma, M., Ishikura, H., Umehara, H., and Domae, N. (1995) J. Biol. Chem. 270, 27326-27331), the role and mechanism of heat shock (HS)-increased c-jun expression in apoptosis was here investigated. HS increased morphological changes compatible with apoptosis in human leukemia HL-60 cells, and induced ceramide generation and sphingomyelin hydrolysis with an increase of neutral magnesium-dependent sphingomyelinase activity. When HS failed to induce apoptosis in HS-resistant HL-60 cells, ceramide generation was not detected, suggesting that ceramide was involved in downstream signals required for HS-induced apoptosis. Both HS and N-acetylsphingosine (C(2)-ceramide) increased the expression of c-jun/c-fos mRNAs with the peak 2 h after treatment. When we examined whether the inhibition of c-jun expression by its antisense oligodeoxynucleotides (AS) blocked HS- or C(2)-ceramide-induced apoptosis, AS of c-jun gene inhibited apoptotic morphological changes and DNA fragmentation whereas did not sense oligodeoxynucleotides. Moreover, a synthetic tetrapeptide, acetyl-Asp-Met-Gln-Asp-aldehyde (DMQD-CHO), which inhibited the formation of active form of caspase-3 more efficiently than those of caspase-4, -6, -7, and -8, blocked both caspase-3 like activity, c-jun expression and apoptosis induced by HS or C(2)-ceramide, although DMQD-CHO did not affect HS-induced ceramide generation. These results suggested that the ceramide was generated through sphingomyelin hydrolysis by HS-activated neutral, magnesium-dependent sphingomyelinase and that subsequent c-jun expression through activation of caspase-3 played a role in HS-induced HL-60 cell apoptosis.

Apoptosis↗

PubMedDate not supplied

A low calcium environment enhances AP-1 transcription factor-mediated gene expression in the development of osteoblastic MC3T3-E1 cells.

Animals fed a low calcium diet develop hypocalcemia and osteoporotic bone. Earlier we conjectured that a low calcium environment might be one of the factors causing abnormalities in hard tissues. Osteoblastic MC3T3-E1 cells (E1 cells) undergo a process of proliferation and differentiation and then produce small mineralized nodules. In this study, we examined the effects of a low calcium environment on osteoblast-like cells cultured with 10% fetal bovine serum and ascorbic acid. Under the culture condition, nodules with characteristics of normal bone appeared by day 30 regardless of the calcium conditions. However, the low calcium environment enhanced the mRNA expressions of c-fos, c-jun and osteocalcin, a specific marker of the osteoblast phenotype. And the exposure to the low calcium medium inhibited the formation of bone nodules. We further studied the differential expressions of c-fos and c-jun in relation to their responses to serum as a function of phenotypic development in the low calcium environment. Both c-fos and c-jun expressions were highly activated by treatment with epidermal growth factor (EGF), but the magnitude of activation was significantly larger under the low calcium condition than the normal condition at each stage. In addition, DNA-binding activities of activating protein-1 (AP-1), Fos/Jun family dimers, were also accelerated by EGF treatment in the low calcium environment. Our findings suggested that osteocalcin, a bone formation marker, c-fos and c-jun genes, and family protein products (AP-1) interacted to restore the normal cell function which deteriorated in the low calcium environment.

Alkaline Phosphatase↗

PubMed2000

Calcium and disease: molecular determinants of calcium crystal deposition diseases.

Deposition of basic calcium phosphate (hydroxyapatite, octacalcium phosphate and tricalcium phosphate) (BCP) and crystalline calcium pyrophosphate dihydrate (CPPD) is associated with a variety of aging-related pathologies, including osteoarthritis, cartilage degeneration and pseudogout. These diseases of calcium deposition serve as some of the best-studied examples of how calcium-regulated changes in gene expression can directly lead to pathogenic consequences. Tissue damage can result when crystals stimulate cells to release matrix-degrading molecules or secrete cytokines that stimulate the release of matrix-degrading molecules. Exposure of cultured cells to crystals induces expression of cellular proto-oncogenes such as c-fos, c-myc and c-jun, by a calcium-dependent mechanism, and this response can be blocked by a potential therapeutic compound, phosphocitrate. Activation of the c-fos and c-jun genes is directly involved in expression of metalloproteinases such as collagenase and stromelysin, suggesting that crystal-mediated activation of these genes is directly involved in pathogenesis. In this review recent advances in the molecular mechanisms responsible for crystal-mediated cell activation are discussed.

Animals↗

PubMed1991

The nuclear protooncogenes c-jun and c-fos as regulators of DNA replication.

Polyomavirus (Py) DNA replication is regulated by its enhancer, which contains an AP1 site, c-Jun and c-Fos, the products of nuclear protooncogenes c-jun and c-fos, form the heterodimeric transcriptional activating factor AP1. Overexpression of c-fos and c-jun genes strongly stimulated Py DNA replication from the Py origin of replication as well as transcription from the Py early promoter through the AP1 binding site. The cAMP response element (CRE)-binding protein CREB stimulated only transcription, not DNA replication, through the CRE under similar conditions. The results indicate that AP1 functions as a regulator of DNA replication and that the mechanism of activation of Py DNA replication by AP1 is distinct from that of activation of transcription from the Py early promoter.

Animals↗

PubMed2001

Inhibition of BRCA1 leads to increased chemoresistance to microtubule-interfering agents, an effect that involves the JNK pathway.

We have developed ribozymes (Rz) that inhibit BRCA1 expression in order to study the role of this gene in chemosensitivity. Two Rz, targeting positions 358 or 5282 of the BRCA1 mRNA, were cloned into the retroviral vector LXSN and lipofected into the breast cancer cell-line HBL100. We obtained 79-99% inhibition of BRCA1 expression, as determined by real-time quantitative PCR and by Western blotting. Decreased expression of BRCA1 led to sensitivity to the DNA damaging agents cisplatin and etoposide, resistance to the microtubule-interfering agents (MIA) taxol and vincristine. The molecular mechanism of resistance to MIA was investigated further by determining the status of the JNK pathway. We found that JNK1 expression was elevated, while JNK2 expression was decreased in Rz-expressing clones compared to controls. We have quantified the mRNA levels of BRCA1, JNK1, 2, MEK-4, -7 and c-jun after treatment with MIA. Vincristine treatment of control cells resulted in transcriptional repression of BRCA1, while the JNK1, 2, MEK-4, -7 and c-jun genes were induced. In Rz-treated cells, only JNK1 and MEK-4 were expressed and none was induced after MIA treatment. We then studied the phosphorylation of c-jun, a downstream effector of the JNK pathway. We observed a strong increase in phosphorylated c-jun after MIA treatment of the control cells but not in BRCA1-Rz treated cells, suggesting inhibition of the JNK pathway. These results show that the BRCA1-JNK pathway is involved in the cytotoxic response to MIA treatment, and inhibition of BRCA1 leads to transcriptional modifications of the JNK pathway.

Antineoplastic Agents↗

PubMed1995

Stimulus-specific expression of inducible transcription factors in identified oxytocin neurones.

The activation of the magnocellular oxytocin system by different physiological stimuli will require specific genomic responses that may or may not reflect the electrical and short-term secretory activity of the neurones. One of the main determinants of synthetic activity is the rate of transcription and this can be altered acutely by the action of inducible transcription factors (iTFs). Having shown that the expression of two iTFs, the protein products of the c-fos and c-jun genes, does not correlate directly to the electrical activity of magnocellular neurones (Luckman et al., 1994) the expression of leucine zipper iTF mRNAs was measured following different stimuli using combined radioactive and non-radioactive in situ hybridization. Stimuli that are dependent on brainstem afferents such as parturition and systemic injection of cholecystokinin caused co-induction of c-fos and c-jun in oxytocin neurones. Mild osmotic stimulation, a stimulus dependent on forebrain afferents, induced c-fos, fos B and jun B, but inhibited c-jun. Similar patterns of leucine zipper iTF expression have been noted in cultured cells following activation of protein kinases C and A, respectively. Input from the brainstem appears to be mediated, at least in part, by noradrenaline acting on alpha(1)-adrenoceptors. While the forebrain inputs are not well characterised they do appear to include a glutaminergic component that may activate a variety of receptors. Interestingly, another member of the leucine zipper family known to be induced by protein kinase A, inducible cAMP early repressor (ICER), that was previously thought to be restricted to the pineal gland, was expressed in magnocellular neurones following osmotic stimulation but not parturition. Furthermore, the differential expression of iTFs is not limited to this family. Osmotic stimulation influences c-fos, but it also causes the expression of NGFI-A and NGFI-B, members of the zinc finger family of iTFs. By contrast, an acute suckling stimulus is able to induce c-fos and NGFI-A, but not nGFI-B.

Animals↗

PubMed2000

Mechanical stress-initiated signal transductions in vascular smooth muscle cells.

Mechanical force is an important modulator of cellular morphology and function in a variety of tissues, and is particularly important in cardiovascular systems. Vascular smooth muscle cell (VSMC) hypertrophy and proliferation contribute to the development of atherosclerosis, hypertension, and restenosis, where mechanical forces are largely disturbed. How VSMCs sense and transduce the extracellular mechanical signals into the cell nucleus resulting in quantitative and qualitative changes in gene expression is an interesting and important research field. Recently, it has been demonstrated that mechanical stress rapidly induced phosphorylation of platelet-derived growth factor (PDGF) receptor, activation of integrin receptor, stretch-activated cation channels, and G proteins, which might serve as mechanosensors. Once mechanical force is sensed, protein kinase C and mitogen-activated protein kinases (MAPKs) were activated, leading to increased c-fos and c-jun gene expression and enhanced transcription factor AP-1 DNA-binding activity. Interestingly, physical forces also rapidly resulted in expression of MAPK phosphatase-1 (MKP-1), which inactivates MAPKs. Thus, mechanical stresses can directly stretch the cell membrane and alter receptor or G protein conformation, thereby initiating signalling pathways, usually used by growth factors. These findings have significantly enhanced our knowledge of the pathogenesis of arteriosclerosis and provided promising information for therapeutic interventions for vascular diseases.

Aging↗

PubMed1996

c-Jun is a downstream target for ceramide-activated protein phosphatase in A431 cells.

Stimulation of [3H]serine-labeled A431 cells with tumor necrosis factor-alpha (TNFalpha) or bacterial sphingomyelinase (SMase) resulted in a rapid decrease (approximately 50% by 15 min) in cellular [3H]sphingomyelin content and generation of the lipid moiety [3H]ceramide, which remained elevated 60 min later. Sphingomyelin hydrolysis in response to TNFalpha or bacterial SMase resulted in a time-dependent decrease in the phosphorylation state of c-Jun protein, an effect that was also observed in cells treated with the membrane-permeable ceramide analogue N-hexanoylsphingosine (C6-ceramide). The rapid dephosphorylation of the c-Jun gene product in response to TNFalpha, SMase, or C6-ceramide was not observed in A431 cells treated with the serine-threonine phosphatase inhibitor okadaic acid. After the initial steps of previously described methods for the purification of a ceramide-activated protein phosphatase termed CAPP (Dobrowsky, R. T., Kamibayashi, C., Mumby, M. C., and Hannun, Y. A. (1993) J. Biol. Chem. 268, 15523-15530), we obtained a cytosolic fraction from A431 cells that specifically dephosphorylated 32Pi-labeled c-Jun protein used as substrate in an immunocomplex phosphatase assay. Phosphatase activity in vitro was apparent only in the presence of ceramide (5 micro) and was specifically abrogated when okadaic acid (1 n) was included in the immunocomplex phosphatase assay. These results provide strong evidence for c-Jun as a downstream target for CAPP activated in response to post-TNF signaling in A431 cells.

Bacteria↗

PubMed1993

Induction and nuclear accumulation of fos and jun proto-oncogenes in hypoxic cardiac myocytes.

Hypoxic and ischemic stresses cause a series of well documented changes in myocardial cells and tissues, including increased anaerobic glycolysis, loss of contractility, changes in lipid and fatty acid metabolism, and eventual irreversible membrane damage and cell death. In this article we describe changes in the expression and regulation of the proto-oncogenes fos and jun in cardiac myocytes exposed to severe hypoxia. The mRNAs encoding c-Fos, c-Jun, Jun-D, and Jun-B were induced within 1 h of exposure to hypoxia, increased 5-10-fold between 1 and 4 h and then declined. These inductions coincided with loss in myocyte contractility but occurred before there was irreversible cell damage or significant ATP loss. Immunostaining with anti-Fos and anti-Jun antibodies revealed the accumulation of these proteins in hypoxic cell nuclei. Pre-treatment of cells with protein kinase inhibitors significantly repressed the response at the mRNA level. We propose that hypoxic stress in these cells activates signal transduction pathways, possibly involving protein kinases, that result in the inductions of fos and jun gene families. Therefore AP1 may regulate myocardial adaptive responses to hypoxia in advance of energy depletion, cell damage, or reoxygenation.

Animals↗

PubMed1997

BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C.

Big MAP kinase 1 (BMK1), also known as ERK5, is a mitogen-activated protein (MAP) kinase member whose biological role is largely undefined. We have shown previously that the activity of BMK1 in rat smooth muscle cells is up-regulated by oxidants. Here, we describe a constitutively active form of the MAP kinase kinase, MEK5(D), which selectively activates BMK1 but not other MAP kinases in vivo. Through utilization of MEK5(D), we have determined that a member of the MEF2 transcription factor family, MEF2C, is a protein substrate of BMK1. BMK1 dramatically enhances the transactivation activity of MEF2C by phosphorylating a serine residue at amino acid position 387 in this transcription factor. Serum is also a potent stimulator of BMK1-induced MEF2C phosphorylation, since a dominant-negative form of BMK1 specifically inhibits serum-induced activation of MEF2C. One consequence of MEF2C activation is increased transcription of the c-jun gene. Taken together, these results strongly suggest that in some cell types the MEK5/BMK1 MAP kinase signaling pathway regulates serum-induced early gene expression through the transcription factor MEF2C.

3T3 Cells↗

PubMed1994

junB promoter regulation: Ras mediated transactivation by c-Ets-1 and c-Ets-2.

The Jun gene family encode components of the AP-1 transcription factor complex that regulate a variety of TRE-containing target promoters. Expression of family members is induced by a wide variety of extracellular stimuli and thought to be important in mediating cellular proliferation and differentiation. We have localized cis-acting DNA sequences in the murine junB promoter capable of mediating transcriptional activation by the proto-oncogene products c-Ets-1 and c-Ets-2. We show by promoter deletion analysis that multiple elements located between -848 and -574, and between -196 and -91 can mediate transactivation by ETS-family members in different cell types. In vitro DNA binding assays indicate that the elements identified can specifically interact with c-Ets-1 protein. Furthermore, we show that ETS-transactivation of a variety of reporter constructs is dramatically enhanced by introduction of oncogenic Ha-ras. The activation of Ras by extracellular stimuli invokes a phosphorylation cascade that includes the downstream mitogen-activated protein (MAP) kinase p44ERK-1. We further show that addition of activated p44ERK-1 MAP kinase can also enhance ETS-transactivation of junB promoter reporter constructs. Here we propose that ETS-family members play a role in the activation of junB transcription by a Ras-stimulated signal transducing pathway that includes MAP kinase(s).

Animals↗

PubMed1998

Signal transduction in arteriosclerosis: mechanical stress-activated MAP kinases in vascular smooth muscle cells (review).

Vascular smooth muscle cell (SMC) proliferation is a key event in the development of (spontaneous) atherosclerosis, hypertension-related arteriosclerosis, angioplasty-induced restenosis and venous bypass graft arteriosclerosis. Many factors or environmental stimuli are believed to be responsible for SMC growth or hypertrophy in the vessel wall. How these environmental stimuli or signals applied onto the surface of SMCs are transduced into the cell nucleus resulting in quantitative and qualitative changes in gene expression in SMCs of arterial walls is largely unknown. Mitogen-activated protein (MAP) kinases are rapidly activated in cells stimulated with various extracellular signals by dual phosphorylation of tyrosine and threonine residues. They are thought to play a pivotal role in transmitting transmembrane signals required for cell growth and differentiation. Recent studies have focused on the signalling events in vascular tissues in vivo and in cultured SMCs in vitro. It has been demonstrated that acute hypertension and angioplasty rapidly induced MAP kinase activation in the arterial wall. Kinase activation is followed by an increase in c-fos and c-jun gene expression and enhanced transcription factor AP-1 DNA-binding activity. A similar MAP kinase activation can be mimicked in in vitro cultured SMCs stimulated by either shear stress or cyclic strain stretch, suggesting direct effects of mechanical force. Interestingly, physical forces rapidly resulted in phosphorylation of platelet-derived growth factor (PDGF) receptor, an activated state, in cultured SMCs. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signalling pathways usually used by growth factors. These findings have significantly enhanced our knowledge concerning the pathogenesis of arteriosclerosis and provide a basis for therapeutic intervention on vascular diseases.

Angioplasty↗

PubMed1998

The modulatory role of nitric oxide in the regulation of proenkephalin and prodynorphin gene expressions induced by kainic acid in rat hippocampus.

The effect of L-arginine (L-ARG), a nitric oxide donor, or Nomega-nitro-L-arginine (L-NAME), a nitric oxide synthase inhibitor, on the regulation of kainic acid (KA)-induced proenkephalin (proENK) and prodynorphin (proDYN) mRNA expressions in rat hippocampus was studied. The proENK and proDYN mRNA levels were markedly increased 6 h after KA (10 mg/kg, i.p.) administration. The elevations of both proENK and proDYN mRNA levels induced by KA was effectively inhibited by pre-administration of L-ARG (400 mg/kg, i.p.), but was not affected by pre-treatment with L-NAME (200 mg/kg, i.p.). The blockade of KA-induced proENK and proDYN mRNA levels by the pre-treatment with L-ARG was well correlated with proto-oncoprotein levels, such as c-Fos, Fra-2, FosB, JunD, JunB, and c-Jun, as well as AP-1 and ENKCRE-2 DNA binding activities. The pre-administration with L-NAME further increased KA-induced c-jun and c-fos mRNA levels in addition to their protein product levels, although the pre-treatment with L-NAME did not affect KA-induced FosB, Fra-2, JunB, and JunD protein levels at 6 h after treatment. In addition, the pre-administration with L-NAME further increased the KA-induced AP-1 and ENKCRE-2 DNA binding activities. Our results suggest that L-ARG plays an important role in inhibiting KA-induced proENK or proDYN mRNA expression, and its inhibitory action may be mediated through reducing the proto-oncoprotein levels, such as c-Fos, Fra-2, FosB, c-Jun, JunD, and JunB. In addition, L-NAME potentiated the c-Fos or c-Jun gene expression, as well as AP-1 or ENKCRE-2 DNA binding activity. However, these increases did not show the potentiative effect on KA-induced increases of proENK and proDYN mRNA level.

Animals↗

PubMed2004

Dominant-negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation.

Activation of the transcription factor AP-1 (activator protein-1) is required for tumor promotion and maintenance of malignant phenotype. A number of AP-1-regulated genes that play a role in tumor progression have been identified. However, AP-1-regulated genes driving tumor induction are yet to be defined. Previous studies have established that expression of a dominant-negative c-Jun (TAM67) inhibits phorbol 12-tetradecanoyl-13-acetate (TPA)-induced AP-1 transactivation as well as transformation in mouse epidermal JB6/P+ cells and tumor promotion in mouse skin carcinogenesis. In this study, we utilized the tumor promotion-sensitive JB6/P+ cells to identify AP-1-regulated TAM67 target genes and to establish causal significance in transformation for one target gene. A 2700 cDNA microarray was queried with RNA from TPA-treated P+ cells with or without TAM67 expression. Under conditions in which TAM expression inhibited TPA-induced transformation, microarray analysis identified a subset of six genes induced by TPA and suppressed by TAM67. One of the identified genes, the high-mobility group protein A1 (Hmga1) is induced by TPA in P+, but not in transformation-resistant P cells. We show that TPA induction of the architectural transcription factor HMGA1 is inhibited by TAM67, is extracellular-signal-regulated kinase (ERK)-activation dependent, and is mediated by AP-1. HMGA1 antisense construct transfected into P+ cells blocked HMGA1 protein expression and inhibited TPA-induced transformation indicating that HMGA1 is required for transformation. HMGA1 is not however sufficient as HMGA1a or HMGA1b overexpression did not confer transformation sensitivity on P- cells. Although HMGA1 expression is ERK dependent, it is not the only ERK-dependent event required for transformation because it does not suffice to rescue ERK-deficient P- cells. Our study shows (a) TAM 67 when it inhibits AP-1 and transformation, targets a relatively small number of genes; (b) HMGA1, a TAM67 target gene, is causally related to transformation and therefore a potentially important target for cancer prevention.

Animals↗