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PubMed2026

Enhancer-mediated DDIT4 activation by SMYD2-dependent H3K4me1 promotes pazopanib resistance in clear cell renal cell carcinoma.

BACKGROUND: The progression and resistance to targeted therapy, including pazopanib, frequently lead to poor prognosis in clear cell renal cell carcinoma (ccRCC) patients. However, the underlying molecular mechanisms of these processes remain unclear. METHODS: In this study, we first performed RNA-seq to identify genes that were differentially expressed in both SMYD2-knockdown and pazopanib-resistant cells, indicating their potential role in SMYD2-mediated drug resistance. We analyzed TCGA-KIRC data and 150 patient samples to identify the relationship between SMYD2 and DDIT4 expression levels, as well as the prognostic significance of DDIT4. In vitro functional assays and murine models were applied to evaluate the effects of SMYD2 and DDIT4 on tumor growth and on pazopanib resistance. CUT&Tag and chromosome conformation capture (4 C) assays were applied to identify enhancers associated with SMYD2-mediated regulation of DDIT4, while the JASPAR database was utilized to predict transcription factors involved in the enhancer regulation. CRISPR-mediated enhancer deletion and ChIP-qPCR were subsequently performed to validate the regulatory roles of the identified enhancer and the transcription factor SPI1 in DDIT4 expression. RESULTS: Our study revealed that the expression level of DDIT4 is positively correlated with SMYD2. DDIT4 is highly expressed in renal cell carcinoma and is associated with poorer survival outcomes. Further research revealed that SMYD2 regulates H3K4me1 in a DDIT4 distal enhancer (chr10:72830412-72830891), promoting the recruitment of the transcription factor SPI1, thereby activating DDIT4 expression. We found that DDIT4 promotes the proliferation, metastasis, and pazopanib resistance of ccRCC, and DDIT4 knockdown enhances drug sensitivity in both in vitro and in vivo experiments. Furthermore, the SMYD2-DDIT4 axis activates the downstream STAT3 signaling pathway, thereby promoting tumor progression. In addition, DDIT4-related prognostic features showed potential associations with patient survival and predicted drug sensitivity in computational analyses. CONCLUSIONS: Our study identifies a previously unrecognized SMYD2-enhancer-DDIT4 regulatory axis, which promotes tumor progression and pazopanib resistance in ccRCC. These findings may provide potential therapeutic implications to overcome pazopanib resistance and improve treatment outcomes in ccRCC by targeting the SMYD2-enhancer-DDIT4 axis.

Carcinoma, Renal Cell↗

PubMed1996

Identification of a transthyretin enhancer site that selectively binds the hepatocyte nuclear factor-3 beta isoform.

The upstream proximal region of the transthyretin (TTR) promoter and a distal enhancer are sufficient to drive liver-specific expression of the TTR gene, as demonstrated by experiments in transgenic mice. Previous analyses have characterized the binding of a number of liver-enriched transcription factors of the TTR promoter including hepatocyte nuclear factors one (HNF-1), HNF-4, and three distinct HNF-3 proteins (alpha, beta, and gamma), which are members of the winged helix (fork head) family. The TTR enhancer was shown to bind members of the CCAAT/enhancer binding protein (C/EBP) family at two distinct sites (TTR-2 and TTR-3), and an oligonucleotide containing the activation protein one (AP-1) binding sequence competed for recognition to a third enhancer site (TTR-1). In this study, we have carried out a detailed analysis of the transcription factors that recognize the TTR enhancer elements (TTR-1, TTR-2, and TTR-3 oligonucleotide sequences). Analysis of the TTR-1 site demonstrates that the putative AP-1 site in the TTR enhancer binds a ubiquitously expressed factor that is distinct from the AP-1 family of proteins. Next we demonstrate, via gel shift analysis, that the TTR-3 site is recognized by the C/EBP family in liver nuclear extracts. We also show that whereas the TTR-2 enhancer site is capable of binding recombinant C/EBP proteins, it does not bind C/EBP proteins from liver nuclear extracts. The TTR-2 site does, however, contain a variant HNF-3 recognition sequence that exclusively binds the HNF-3 beta isoform. Mutation of this HNF-3 beta-specific recognition sequence caused reductions in TTR enhancer activity. We had previously observed a 95% decrease in HNF-3 alpha expression and a 20% reduction in HNF-3 beta expression in acute phase livers, which correlated with a 60% decrease in TTR gene transcription. We propose that the HNF-3 beta-specific binding site in the TTR enhancer may play a role in maintaining TTR gene expression during the acute phase response in spite of the dramatic reduction in HNF-3 alpha protein levels.

Animals↗

PubMed1996

Invasive breast carcinoma: analysis of dynamic magnetic resonance imaging enhancement features and cell proliferative activity determined by DNA S-phase percentage.

BACKGROUND: There is little information regarding associations between magnetic resonance imaging (MRI) enhancement and biologic parameters of breast carcinoma. A prospective study was undertaken to correlate MRI dynamic contrast enhancement features with cell proliferative activity, as determined by DNA S-phase percentage. METHODS: Seventeen patients with invasive breast cancer underwent MRI at 1.5 tesla using a dynamic gadolinium-enhanced spoiled gradient recall echo technique. DNA analysis of samples of the excised lesions was then performed using flow cytometry. RESULTS: Invasive carcinomas with high DNA S-phase percentages (> or = 6.9%, the median value in this study), a measure of increased cell proliferation, were associated with a peripheral MRI enhancement pattern in 4 of 6 (67%) lesions compared with 0 of 11 carcinomas with lower DNA S-phase percentages (< or = 6.9%) (P = 0.006). There was no significant association between a high DNA S-phase percentage and greater MRI enhancement amplitude, rate, or washout. There was no significant association between aneuploid DNA content and any MRI enhancement feature. CONCLUSIONS: Increased cell proliferation in invasive breast carcinoma, as determined by high DNA S-phase percentage, is significantly associated with a peripheral MRI enhancement pattern but unrelated to greater MRI enhancement amplitude, rate, or washout.

Adult↗

PubMed1997

Lens-preferred activity of chicken delta 1- and delta 2-crystallin enhancers in transgenic mice and evidence for retinoic acid-responsive regulation of the delta 1-crystallin gene.

There are two tandemly linked delta-crystallin genes [5' delta 1 -delta 2 3'] in the chicken, with the delta 1-crystallin gene being expressed much more highly (50-100-fold) in the embryonic lens than the delta 2-crystallin gene. Previous transfection experiments have shown that a lens-preferred enhancer exists in the third intron of each chicken delta-crystallin gene. In the present investigation we have used transgenic mice to establish that both the chicken delta 1- and delta 2-crystallin enhancers are preferentially active in the mouse lens in combination with their homologous promoter and the chloramphenicol acetyltransferase (CAT) reporter gene. The promoter/ CAT constructs lacking the enhancers were inactive in the transgenic mice. In one case, a truncated delta 2-crystallin promoter (-308/+24) in combination with the enhancer was also active in the Purkinje cells of the cerebellum of the transgenic mice, which could prove useful in future experiments. Finally, retinoic acid receptors (RAR beta) activated the delta 1-crystallin, but not the delta 2-crystallin enhancer in teh recombinant plasmids in cotransfected embryonic chicken lens epithelial cells treated with retinoic acid. This activation did not occur when using the care enhancer (fragment B4) lacking surrounding flanking sequences (fragment B3 and B5) of the enhancer. Together these experiments show that the chicken delta-crystallin enhancers show lens-preference in transgenic mice despite the absence of delta-crystallin in this species and add retinoic acid nuclear receptors to the growing list of transcription factors (including Pax-6, Sox-2, and delta EF3) that directly or indirectly contribute to the high expression of the delta 1-crystallin gene in the lens.

Animals↗

PubMed2000

Improved tissue characterization of focal liver lesions with ferumoxide-enhanced T1 and T2-weighted MR imaging.

The purpose of our study was to evaluate the potential value of ferumoxide-enhanced T1-weighted magnetic resonance (MR) imaging for tissue characterization of focal liver lesions when combined with T2-weighted sequences. Images were acquired within 30 minutes after the end of ferumoxide administration, when ferrite particles were not totally cleared from the intravascular compartment. Thirty-eight patients with 47 focal liver lesions underwent T1-weighted gradient-echo (TR/TE 150/4.1 msec) and T2-weighted fast spin-echo (3180-8638/90 msec) MR imaging at 1.5 T before and after intravenous administration of ferumoxides (10 micromol/kg body weight). A qualitative and quantitative analysis was performed. During the early phase after infusion of ferumoxide, blood vessels showed hypersignal intensity on T1-weighted fast low-angle shot (FLASH) images, while liver signal decreased. Hemangiomas showed both homogeneous and inhomogeneous enhancement patterns, and liver metastasis most typically showed ring enhancement. Hypervascular tumors (hepatocellular carcinomas and focal nodular hyperplasias) showed a slight degree of homogeneous enhancement. Quantitatively, the degree of enhancement and lesion-to-liver contrast on ferumoxide-enhanced images were significantly different among these tumors. Our results demonstrate that distinct enhancement patterns obtained on ferumoxide-enhanced T1-weighted MR imaging improve tissue characterization of focal liver lesions when combined with T2-weighted images.

Adult↗

PubMed2000

Detection of focal hepatic lesions: comparison of unenhanced and SHU 555 A-enhanced MR imaging versus biphasic helical CTAP.

The purpose of this study was to compare the diagnostic sensitivity of unenhanced magnetic resonance (MR) imaging, and MR imaging with a new superparamagnetic iron oxide (SPIO)-enhanced contrast agent (SHU 555 A) with biphasic helical computed tomography during arterial portography (CTAP) in patients with focal liver lesions. Eighteen patients with a total of 91 (78 malignant, 13 benign) proven liver lesions underwent unenhanced short tau inversion recovery (STIR), T2-weighted (T2-w) TSE, and SHU 555 A-enhanced T2-w turbo spin-echo (TSE) MR imaging and biphasic helical CTAP. The standard of reference was histopathologic analysis of resected specimens in 59 lesions, intraoperative ultrasound with biopsy in 20 lesions, and CT-guided biopsy and follow-up in 12 lesions. Diagnostic performance of the imaging modalities was compared quantitatively and qualitatively by assessing lesion involvement in liver segments. There were 68 lesions detected on unenhanced T2-w TSE, which resulted in a sensitivity of 75%. With the STIR sequence, 76 lesions were detected, for a sensitivity of 84%, and with SHU 555 A-enhanced MRI, 84 lesions were detected, for a sensitivity of 92%. CTAP detected 88 lesions, for a sensitivity of 97%. The accuracy for unenhanced T2-w TSE was 98%, for STIR 99%, for enhanced-MRI 100%, and for CTAP 95%. The specificity was 100% for SHU 555 A-enhanced MRI and 95% for CTAP. SHU 555 A-enhanced MRI was superior to nonenhanced MRI (P < 0.05) and equivalent to CTAP in terms of sensitivity. Due to the absence of false-positive results on SHU 555 A-enhanced MRI, the specificity and accuracy of enhanced MRI were higher than those of CTAP, but the difference was not statistically significant (P = 0.134).

Adult↗

PubMed1991

The mouse IgH 3'-enhancer.

A lymphoid-specific transcription enhancer element has recently been identified at the far 3' end of the rat immunoglobulin heavy chain (IgH) locus. Sequence analysis presented here reveals that this enhancer is flanked by a 350-bp invert repeat, giving a structure reminiscent of a transposable element. We therefore screened for the equivalent enhancer in the mouse to determine whether its presence was conserved during evolution. A mouse homologue was indeed identified and is located 16 kb downstream of the C alpha 1 exon. It is also flanked by invert repeats and these are not repeated throughout the genome. The mouse and rat enhancers retain high sequence homology. As regard activity, the IgH 3'-enhancer is lymphoid specific. However, this activity was detected in two plasmacytoma lines tested but not in two B cell lymphomas nor in HeLa cells suggesting that the enhancer may only play a stage-specific role during lymphocyte differentiation. As regards function within the IgH locus, we found that inclusion of the mouse IgH 3'-enhancer (in addition to the intron-enhancer) on mu gene expression plasmids effected a small increase in mu mRNA levels in stable plasmacytoma transfectants.

Animals↗

PubMed1994

Lipopolysaccharide-dependent transactivation of the temporally regulated immunoglobulin heavy chain 3' enhancer.

To execute different biological functions, the expression pattern of immunoglobulin heavy chain genes (IgH) is altered during B lymphocyte differentiation. Early in B cell differentiation, it is assumed that the heavy chain promoter and the intragenic enhancer (E mu) ensure VDJ recombination. This leads to the expression of the immunoglobulin receptor on the cell surface. An additional strong enhancer in the far 3' end of the IgH locus has, however, prompted a re-evaluation of the regulation of immunoglobulin gene expression. To define the temporal and spatial regulation of the IgH 3' enhancer, transgenic mice harboring an enhancer-dependent reporter gene construct were generated. Here we demonstrate that IgH 3' enhancer activity is largely restricted to activated immunocompetent B cells. Furthermore, the enhancer can be transactivated following mitogen stimulation with lipopolysaccharide and 12-O-tetradecanoylphorbol 13-acetate. We propose a model whereby 3' enhancer activation is linked to the activation of resting immunocompetent B cells. The implications of the enhancer being active in late B lymphocyte differentiation, when heavy chain class switching occurs, are discussed.

Animals↗

PubMed1985

Specific interaction of cellular factors with the B enhancer of polyoma virus.

Specific interactions between proteins from mouse 3T6 cells and the enhancer sequence of polyoma virus were detected using the method of band shifting on polyacrylamide gels. Proteins eluted from 3T6 nuclei using a buffer containing 0.55 M NaCl, formed a stable complex with the B enhancer of polyoma virus. At least two different factors are involved in this interaction. The contact sites which were mapped on the DNA sequence using DNase I footprinting correspond to a GC-rich palindrome surrounded by two sequences homologous respectively to the immunoglobulin and to the immunoglobulin and SV40 enhancers. Moreover Bal31 deletion analysis confirmed that similar sequences are required for the formation of the complex. In spite of a common function and partial sequence homology among some enhancers, neither the polyoma A enhancer, the mouse immunoglobulin heavy chain gene enhancer, nor the origin-promoter-enhancer region of SV40 efficiently competed with the polyoma B enhancer for the binding of these molecules.

Animals↗

PubMed1985

Cell type-specific transcriptional enhancement in vitro requires the presence of trans-acting factors.

Cell-specific transcriptional enhancement was observed, depending on the enhancer sequences, using nuclear extracts prepared from B-cells, T-cells and HeLa cells. SV40 enhancer stimulated in vitro transcription up to 15-fold in all three cell extracts, whereas transcriptional potentiation in vitro by IgC mu and LPV enhancers was only seen in B- and T-cell extracts. Thus, the cell type specificity seen in vivo can be reproduced in vitro. The transcriptional enhancement requires the presence of enhancer sequences in cis and also of a common factor interacting in trans with all three enhancer sequences. Interestingly, first experiments indicate the additional presence of cellular factors in T-cell and most prominently in HeLa cell extracts which can reduce the enhancer activity of C mu and LPV.

B-Lymphocytes↗

PubMed1987

An enhancer element lies 3' to the human A gamma globin gene.

We have surveyed 22 kb of DNA from the region surrounding the human fetal (gamma) globin genes and have identified one fragment that meets all of the criteria for a non-tissue specific enhancer element. The enhancer-containing fragment starts approximately 400 bp 3' to the polyadenylation signal of the A gamma gene and is less than 750 bp in length. Addition of this fragment to plasmids containing a 'gamma-CAT' hybrid gene [consisting of the gamma globin gene promoter fused to the chloramphenicol acetyl transferase (CAT) gene] increases CAT expression 6-23-fold in K562 erythroleukemia cells, depending upon the method of transfection. The increase in expression is essentially independent of the orientation or position of the fragment with respect to the gamma-CAT hybrid gene. The 3' gamma enhancer activates heterologous promoters in erythroleukemia cells, and is also active in non-erythroid cell lines. The enhancer acts by increasing the number of transcripts initiated from the normal gamma globin gene transcription initiation site. The enhancer region contains two DNase I hypersensitive sites in erythroleukemia cells but none in nonerythroid human leukemia cell lines. The 3' gamma globin gene enhancer contains a unique element that is similar to sequences found in an enhancer 3' to the chicken beta globin gene, suggesting that this conserved element may have a role in enhancer function.

Base Sequence↗

PubMed1990

A 3' transcriptional enhancer regulates tissue-specific expression of the human CD2 gene.

A strong lymphocyte-specific transcriptional enhancer was identified within a DNase I hypersensitive site at the 3' end of the human CD2 gene. Full activity, in a transient expression assay, was contained within a region of 550 bp (minimal enhancer). T cells which express CD2 could use the enhancer to activate transcription from the reporter gene chloramphenicol acetyltransferase in the context of a heterologous promoter. Lower levels of transcription were detected in non-CD2-expressing T cells and in B cells. In contrast, the enhancer did not function in the epithelial cell line HeLa or in Colo 320 HSR, a cell line of neuroendocrine origin. Low levels of enhancement were detectable from two core regions, which acted synergistically with other cis-acting sequences to generate the complete enhancer. DNase I footprinting studies identified six cis-acting sequences to which proteins bound. Five of these sequence motifs were novel; the sixth was a canonical cAMP response element. Topoisomerase II, and scaffold attachment region consensus sequences were also found within an A/T-rich area downstream of the minimal enhancer. Neither region was bound to the nuclear matrix. The CD2 enhancer is modular in structure, it is constructed of novel cis-acting sequences and it is a major component of the regulatory system that controls expression of the CD2 gene.

Base Sequence↗

PubMed1991

Enhancer activation by a single type of transcription factor shows cell type dependence.

Promoter and enhancer elements contain multiple binding sites for ubiquitous and cell type-specific transcription factors which stimulate transcription synergistically. Here we show that cell type-dependent enhancer activity can be achieved by mechanisms other than interactions between cell type-specific transcription factors and DNA. The ability of the SV40 enhancer and the E2 transactivator from bovine papillomavirus (BPV-1) to stimulate transcription from a reporter gene with different minimal promoters was tested in four cell lines. In lymphoid BJA-B cells all minimal promoters that synergized with the SV40 enhancer did so also with the E2-dependent enhancer. In sharp contrast to these results, the E2 enhancer stimulated transcription only from a subset of promoters in fibroblasts and in epithelial cells. The results suggest that lymphoid cells, unlike fibroblasts and epithelial cells, contain auxiliary factor(s) which are necessary for the activation of certain promoters by the E2 enhancer and infer that the specificity of enhancers also is regulated at a co-activator level.

Base Sequence↗

PubMed2004

Comparative cis-regulatory analyses identify new elements of the mouse Hoxc8 early enhancer.

The Hoxc8 early enhancer is a 200 bp region that controls the early phase of Hoxc8 expression during mouse embryonic development. This enhancer defines the domain of Hoxc8 expression in the neural tube and mesoderm of the posterior regions of the developing embryo. Five distinct cis-acting elements, A-E, were previously shown to govern early phase Hoxc8 expression. Significant divergence between mammalian and fish Hoxc8 early enhancer sequences and activities suggested additional cis-acting elements. Here we describe four additional cis-acting elements (F-I) within the 200 bp Hoxc8 early enhancer region identified by comparative regulatory analysis and transgene-mutation studies. These elements affect posterior neural tube and mesoderm expression of the reporter gene, either singly or in combination. Surprisingly, these new elements are missing from the zebrafish and Fugu Hoxc8 early enhancer sequences. Considering that fish enhancers direct robust reporter expression in transgenic mouse embryos, it is tempting to postulate that fish and mammalian Hoxc8 early enhancers utilize different sets of elements to direct Hoxc8 early expression. These observations reveal a remarkable plasticity in the Hoxc8 early enhancer, suggesting different modes of initiation and establishment of Hoxc8 expression in different species. We postulate that extensive restructuring and remodeling of Hox cis-regulatory regions occurring in different taxa lead to relatively different Hox expression patterns, which in turn may act as a driving force in generating diverse axial morphologies.

Animals↗

PubMed2004

Magnetic resonance portography using contrast-enhanced fat-saturated three-dimensional steady-state free precession imaging.

PURPOSE: To assess the feasibility of contrast-enhanced fat-saturated three-dimensional steady-state free precession (FIESTA) imaging for contrast-enhanced magnetic resonance (MR) portography. MATERIALS AND METHODS: Contrast-enhanced fat-saturated three-dimensional fast spoiled gradient-echo (SPGR) and FIESTA were performed as MR portography. In 10 cases, fat-saturated three-dimensional FIESTA was first performed and followed by fast SPGR, and the order of post-contrast imaging was reversed in the other 10 cases. Signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) were estimated for portal and visceral veins on the source images. The visualization of portal vein was scored on three-dimensional MR portography. Portal venous system disorders were assessed using three-dimensional MR portography. RESULTS: The SNRs, CNRs, and visual assessment of portal and visceral veins were significantly higher in contrast-enhanced fat-saturated three-dimensional FIESTA than contrast-enhanced fat-saturated three-dimensional fast SPGR (P < 0.05). The contrast-enhanced fat-saturated three-dimensional FIESTA provided high venous signals even at 8 minutes after gadolinium injection. The abnormalities of portal venous system were well visualized with MR portography using contrast-enhanced fat-saturated three-dimensional FIESTA. CONCLUSION: Contrast-enhanced fat-saturated three-dimensional FIESTA was valuable for MR portography, with flexible time window and high vascular signals. This imaging may allow for other post-contrast imaging options before portography and release patients from consecutive breath-holds.

Adult↗

PubMed2000

Human histo-blood group ABO glycosyltransferase genes: different enhancer structures with different transcriptional activities.

The enhancer element of the human histo-blood group ABO glycosyltransferase gene has been demonstrated to be located -3.7 kb upstream from the transcription start site and to be composed of four tandem repeats of a 43-bp unit. Recently we identified three different enhancer structures among the allelic A, B, and O glycosyltransferase genes. The enhancer structure with four 43-bp units is present in the B and O genes, but not in the A gene. The corresponding enhancer region of the A gene contains only one 43-bp unit, and within this unit a nucleotide substitution exists when compared with the consensus sequence. Through transient transfection assays, the transcriptional activity of the A-gene enhancer region was demonstrated to be less than 1% of that of the B-gene enhancer. The difference between the transcriptional activities of the two enhancers became more significant when acting in concert with the ABO-gene's native promoter. The different repeat numbers of the 43-bp unit possessed by the two allelic genes were shown to be the main reason for the vast difference in the transcriptional activities between the A-gene and B-gene enhancers.

ABO Blood-Group System↗

PubMed1995

Hepatitis B virus enhancer binds and is activated by the Hepatocyte nuclear factor 3.

The enhancer of hepatitis B (HBV) virus displays a liver-specific activity that determines the postreceptor virus-host tropism. Despite the detailed study of this enhancer our knowledge of the mechanisms underlying this behavior is very limited. Here we report that the hepatocyte nuclear factor 3 (HNF3) is at least in part responsible for the liver-specific activity of the enhancer. We demonstrate that recombinant HNF3 alpha binds the enhancer at two sites with different affinity. Transfection studies have demonstrated that the enhancer is active only in liver cells and that integrity of the HNF3 binding sites is important for its full activity. In vitro transcription assays revealed that the enhancer is active only in liver extracts but not in extracts prepared from HeLa cells. Furthermore, the latter extract cannot be activated by addition of recombinant HNF3 alpha. A similar behavior is manifested in transfected cells and, here again, the inactive enhancer is not activated by cotransfected HNF3 beta and alpha. Collectively, our study shows that HNF3 activators are required but not sufficient for full activation of the HBV enhancer and there is a need for additional liver-specific activators or coactivators.

Base Sequence↗

PubMed1995

Transcriptional activity of human papillomavirus type 31b enhancer is regulated through synergistic interaction of AP1 with two novel cellular factors.

Transcription of human papillomaviruses (HPV) is regulated by enhancer sequences located in the upstream regulatory region. The factors regulating expression of one of the high risk genital HPV types, HPV 31b, were investigated using transient expression and protein binding assays. A region of 262 base pairs in length was identified as the minimal functional enhancer and a series of five protected binding sites were observed by footprint analyses. Electrophoretic mobility shift assays demonstrated that AP1, Oct-1, as well as three novel factors bound these sequences. Mutational analyses indicated that AP1 synergistically activated the HPV31b enhancer together with either of two novel factors. One of these novel factors bound a sequence similar to an NF1 site but was distinct from NF-1. The second factor bound sequences bearing similarity to KRF-1 binding sites which have previously been characterized in HPV 18. Competition binding assays demonstrated that this factor was not identical to KRF-1. Additional studies implicated Oct-1 as a negative regulator of HPV 31b expression as mutation of Oct-1 binding sequences resulted in an increase in viral expression. None of the factors observed to be important for HPV 31b enhancer activity was found exclusively in epithelial cells and instead were detected in a variety of cell types. Of these factors, AP1 binding correlated most strongly with enhancer function in a variety of cell types, implicating it as a principal regulator of HPV expression. Variations in the constituents of the AP1 complex that bind the HPV 31b enhancer were also observed in different cell types, suggesting that changes in the distribution of jun proteins may play a significant role in determining the tropism of HPV. These results indicate that AP1 may be a common regulator for various HPV types and that it contributes to enhancer specificity. In addition, a set of novel factors, which may be specific for each HPV type, act synergistically with AP1 for full activation of the enhancer.

Base Sequence↗