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PubMed2006

Targeting epigenetic abnormalities with histone deacetylase inhibitors.

BACKGROUND: Alterations in chromosome structure play critical roles in the control of gene transcription. These "epigenetic" alterations include modification of histones and other proteins by acetylation and/or phosphorylation. Normally, these modifications are balanced finely and are highly reversible in normal tissues, but they may be imbalanced and heritable in tumor cells. Histone deacetylase inhibitors increase histone acetylation, thereby modulating the expression of a subset of genes in a coordinated fashion. Several tumor suppressor genes associated with the malignant phenotype are repressed by epigenetic mechanisms in sporadic cancers. Thus, therapy with histone deacetylase inhibitors may alter tumor phenotype to inhibit growth in such tumors. METHODS: The authors reviewed the rationale for histone deacetylase inhibitors as potential anticancer agents and reviewed some preclinical and early clinical trial data with various classes of histone deacetylase inhibitors. RESULTS: Preclinical and clinical antitumor activity has been observed. Toxicities include fatigue, myelosuppression, and cardiac abnormalities. CONCLUSIONS: Histone deacetylase inhibitors have shown promising activity in some solid tumors and hematologic malignancies.

Acetylation↗

PubMed1994

Epigenetic effects in eukaryotic gene expression.

In the broadest terms, epigenetic phenomena in eukaryotes depend on the interaction of alleles or repeated sequences or on the mitotic inheritance of chromatin states or methylation patterns. One of the most exciting aspects of the study of epigenetic phenomena is the insight that can be gained into the structure and assembly of higher-order chromatin structures, an important subject that has proved refractory to current biochemical methodologies. Rapid progress in the study of gene inactivation in fungi, plants, and invertebrates will provide new hypotheses to be tested in mammals.

Animals↗

PubMed2003

Multipoint methylation analysis indicates a distinctive epigenetic phenotype among testicular germ cell tumors and testicular malignant lymphomas.

Hypermethylation of tumor-suppressor genes has been implicated in the pathogenesis of human cancers. Although a growing number of genes showing hypermethylation is being reported in human cancer, methylation profiles of tumor-related genes in testicular neoplasms have not been well elucidated. This study was designed to show the methylation profiles of multiple CpG islands in testicular germ cell tumors (TGCTs) in comparison with those in testicular malignant lymphomas. We studied the methylation status of E-cadherin, CDKN2B, CDKN2A, BRCA1, RB1, VHL, RASSF1A, RARB, and GSTP1 by use of TGCT tissues and testicular malignant lymphoma tissues (25 primary TGCT tissues and three primary testicular lymphoma tissues). Methylation was not observed in E-cadherin, CDKN2B, CDKN2A, BRCA1, RB1, VHL, RASSF1A, RARB, and GSTP1 in any of the TGCT tissues. In contrast, all three (100%) of the testicular lymphoma tissues demonstrated hypermethylation of E-cadherin, RASSF1A, and RARB, but not CDKN2B, CDKN2A, BRCA1, RB1, VHL, and GSTP1. These data demonstrate that a distinctive epigenetic phenotype underlies the TGCTs and testicular lymphomas at the CpG sites of E-cadherin, RASSF1A, and RARB; a distinctive epigenetic phenotype was not observed among seminomatous TGCTs and non-seminomatous TGCTs at the CpG sites examined.

Cell Transformation, Neoplastic↗

PubMed2004

Epigenetic regulation of human telomerase reverse transcriptase promoter activity during cellular differentiation.

The human telomerase reverse transcriptase (TERT) gene is transcriptionally inactivated in most differentiated cells but is reactivated in the majority of cancer cells. To elucidate how TERT is inactivated during differentiation, we applied all-trans retinoic acid (ATRA) to induce the differentiation of human teratocarcinoma (HT) cells and human acute myeloid leukemia (HL60) cells. We first showed that TERT promoter activity decreased rapidly, which preceded a gradual loss of endogenous telomerase activity following ATRA induction. To elucidate the underlying mechanisms of the reduced TERT promoter activity during differentiation, we performed epigenetic studies on the TERT promoter and found a progressive histone hypoacetylation coupled with a gradual accumulation of methylated cytosines in the TERT promoter. We also observed that the TERT promoter was less methylated in pluripotent HT cells than in multipotent HL60 cells throughout a 12-day differentiation process. This origin-dependent epigenetic change was also confirmed in histone acetylation studies, indicating that the TERT promoter was more resistant to deacetylation in HT cells than in HL60 cells. Taken together, our results demonstrate synergistic involvement of DNA methylation and histone deacetylation in the down-regulation of TERT promoter activity that may be dependent on the origin of the cell types, and they add new insight into the way telomerase activity may be regulated during differentiation.

Acetylation↗

PubMed2005

Genetic and epigenetic alteration of the NF2 gene in sporadic meningiomas.

The role of the NF2 gene in the development of meningiomas has recently been documented; inactivating mutations plus allelic loss at 22q, the site of this gene (at 22q12), have been identified in both sporadic and neurofibromatosis type 2-associated tumors. Although epigenetic inactivation through aberrant CpG island methylation of the NF2 5' flanking region has been documented in schwannoma (another NF2-associated neoplasm), data on participation of this epigenetic modification in meningiomas are not yet widely available. Using methylation-specific PCR (MSP) plus sequencing, we assessed the presence of aberrant promoter NF2 methylation in a series of 88 meningiomas (61 grade I, 24 grade II, and 3 grade III), in which the allelic constitution at 22q and the NF2 mutational status also were determined by RFLP/microsatellite and PCR-SSCP analyses. Chromosome 22 allelic loss, NF2 gene mutation, and aberrant NF2 promoter methylation were detected in 49%, 24%, and 26% of cases, respectively. Aberrant NF2 methylation with loss of heterozygosity (LOH) at 22q was found in five cases, and aberrant methylation with NF2 mutation in another; LOH 22q and the mutation were found in 16 samples. The aberrant methylation of the NF2 gene also was the sole alteration in 15 samples, most of which were from grade I tumors. These results indicate that aberrant NF2 hypermethylation may participate in the development of a significant proportion of sporadic meningiomas, primarily those of grade I.

Chromosome Aberrations↗

PubMed2005

Genetic and epigenetic alterations of the candidate tumor-suppressor gene MYO18B, on chromosome arm 22q, in colorectal cancer.

Allelic imbalance (AI) on chromosome arm 22q has been detected in 20%-40% of colorectal cancers, suggesting that this chromosome arm has a tumor-suppressor gene involved in colorectal carcinogenesis. Recently, we isolated a candidate tumor-suppressor gene, MYO18B, at 22q12.1, that is deleted, mutated, and hypermethylated in more than 50% of lung cancers. In the present study, we analyzed genetic and epigenetic alterations of the MYO18B gene in colorectal cancers. AI at the MYO18B locus was detected in 16 of 43 (40%) informative cases. Mutations of the MYO18B gene were detected in 2 of 11 (18%) cell lines and 1 of 47 (2%) surgical specimens. Nine of 11 (82%) cell lines showed reduced MYO18B expression, which was restored in all 9 by treatment with 5-aza-2'-deoxycytidine and/or trichostatin A (TSA). Although hypermethylation of the promoter CpG island for MYO18B was not detected, a significant correlation was observed between the level of MYO18B expression and the level of acetylation of histones H3 and H4 in 6 cell lines with and without TSA treatment. Thus, it was suggested that MYO18B is inactivated in a considerable fraction of colorectal cancers by several mechanisms, especially silencing by histone deacetylation and/or AI. Furthermore, restoration of MYO18B expression in colorectal cancer cell lines HT29 and DLD-1 suppressed anchorage-independent growth, whereas it did not affect the growth rate in vitro. These results suggest that genetic and epigenetic inactivation of the MYO18B gene play an important role in colorectal carcinogenesis.

Acetylation↗

PubMed2003

Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse.

Genome-wide epigenetic reprogramming by demethylation occurs in early mouse embryos and primordial germ cells. In early embryos many single-copy sequences become demethylated both by active and passive demethylation, whereas imprinted gene methylation remains unaffected. In primordial germ cells single-copy and imprinted sequences are demethylated, presumably by active demethylation. Here we investigated systematically by bisulphite sequencing the methylation profiles of IAP and Line1 repeated sequence families during preimplantation and primordial germ cell development. Whereas Line1 elements were substantially demethylated during both developmental periods, IAP elements were largely resistant to demethylation, particularly during preimplantation development. This may be desirable in order to prevent IAP retrotransposition, which could cause mutations. In turn, this can result in the transgenerational inheritance of epigenetic states of IAPs, which could lead to heritable epimutations of neighbouring genes through influencing their transcriptional states.

Alleles↗

PubMed2003

Oligodendrocyte process outgrowth in vitro is modulated by epigenetic regulation of cytoskeletal severing proteins.

Process outgrowth is crucial in oligodendrocyte (OL) development and myelination. It is well accepted that increased levels of proteins affecting the polymerization of cytoskeletal components promote branching. Interestingly, we have suggested that other mechanisms may contribute to oligodendrocyte process outgrowth. We have previously shown that pharmacological inhibitors of histone deacetylation prevent oligodendrocyte branching and we now seek to explore in detail the relationship between these two events. The results presented here indicate that pharmacological inhibitors of histone deacetylation prevent branching, similar to the effect of low doses of cytoskeletal depolymerizing agents. The lack of process outgrowth does not correlate with changes in the levels of tubulin or actin, but correlates with increased levels of microtubule (i.e., stathmin) and microfilaments (i.e., gelsolin) depolymerizing proteins. These data suggest that in OL progenitors, the high levels of depolymerizing proteins maintain a simple morphology, while branching is favored by reduced levels of these cytoskeletal components, consequent to the effect of histone deacetylation on gene expression. We therefore hypothesize that epigenetic regulation of stathmin and gelsolin is a novel regulatory mechanism contributing to OL process outgrowth. In conclusion, our results suggest that process outgrowth in vitro is regulated not only by increased levels of proteins affecting polymerization, but also by decreased levels of proteins affecting depolymerization. The levels of these severing proteins are regulated by chromatin modifiers and therefore suggest that their expression in developing OL is decreased by an epigenetic mechanism.

Animals↗

PubMed2003

Epigenetic detection of human chromosome 14 uniparental disomy.

The recent demonstration of genomic imprinting of DLK1 and MEG3 on human chromosome 14q32 indicates that these genes might contribute to the discordant phenotypes associated with uniparental disomy (UPD) of chromosome 14. Regulation of imprinted expression of DLK1 and MEG3 involves a differentially methylated region (DMR) that encompasses the MEG3 promoter. We exploited the normal differential methylation of the DLK1/MEG3 region to develop a rapid diagnostic PCR assay based upon an individual's epigenetic profile. We used methylation-specific multiplex PCR in a retrospective analysis to amplify divergent lengths of the methylated and unmethylated MEG3 DMR in a single reaction and accurately identified normal, maternal UPD14, and paternal UPD14 in bisulfite converted DNA samples. This approach, which is based solely on differential epigenetic profiles, may be generally applicable for rapidly and economically screening for other imprinting defects associated with uniparental disomy, determining loss of heterozygosity of imprinted tumor suppressor genes, and identifying gene-specific hypermethylation events associated with neoplastic progression.

Chromosomes, Human, Pair 14↗

PubMed2003

Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: relationships with abnormal E-cadherin and catenin expression and microsatellite instability.

The causes and functional consequences of E-cadherin (E-CD) loss in breast cancer are poorly understood. E-CD loss might act in concert with alterations in the APC/beta-catenin pathway to permit oncogenic beta-catenin signaling. To test this hypothesis, we have analyzed the presence of genetic and epigenetic alterations affecting E-CD (CDH1), APC and beta-catenin (CTNNB1) genes and the immunohistochemical expression of E-CD, beta- and gamma-catenin in a series of 46 infiltrating lobular breast carcinomas (ILCs). Since 80% of ILCs featured complete loss of E-CD expression, we analyzed the molecular alterations responsible for E-CD inactivation in these tumors. We found that 10 of 46 (22%) cases harbored mutations in CDH1, including 1 case with 2 different mutations (1 of which was germline). CDH1 was also inactivated by loss of heterozygosity (LOH; 30/41, 73%) and promoter hypermethylation (19/46, 41%). Interestingly, LOH and mutations were also detected in the corresponding in situ lesions of the ILCs, implying that these alterations are early events in lobular cancer tumorogenesis. Additionally, the presence of a polymorphism in the CDH1 promoter was found to be inversely correlated with CDH1 mutations, but not with E-CD levels. We next examined whether alterations in the APC/beta-catenin pathway also occurred in the same series of ILCs. Although no CTNNB1 or APC mutations were detected, promoter methylation (25/46, 52%) and LOH (7/30, 23%) of APC were found. Moreover, methylation of APC and CDH1 occurred concordantly. However, beta- and gamma-catenin were severely reduced or absent in 90% of these tumors, implying that alterations in CDH1 and APC genes do not promote beta-catenin accumulation in ILC. These molecular alterations were not associated with microsatellite instability. In summary, several different mechanisms (mutations, LOH, methylation) are involved in the frequent CDH1 inactivation in invasive and in situ lobular breast cancer. The same tumors also show genetic and epigenetic alterations of APC gene. However, altered CDH1 and APC genes do not promote beta-catenin accumulation in this tumor type.

Adenomatous Polyposis Coli Protein↗

PubMed2005

Allele loss and epigenetic inactivation of 3p21.3 in malignant liver tumors.

Previously, the RASSF1A, BLU and SEMAPHORIN 3B (SEMA3B) candidate tumor suppressor genes on chromosome 3p21.3 were found to be inactivated and downregulated by genetic and epigenetic changes in lung cancer. We analyzed the methylation status of RASSF1A, BLU and SEMA3B in 35 hepatocellular carcinomas (HCCs) and 15 cholangiocarcinomas (CCs) by methylation-specific PCR and loss of heterozygosity (LOH) at 3p21.3 after microdissection. The presence of mRNA transcripts was confirmed by semiquantitative PCR. SEMA3B hypermethylation was found in 29/35 HCCs (83%) and in all (15/15) patients with CC. BLU promoter hypermethylation was detected in 7/35 (20%) HCCs and 3/15 (20%) CCs. In 2 corresponding specimens of hepatitis B virus-related liver cirrhosis, BLU methylation was also observed, but not in uninvolved normal liver tissue. RASSF1A was methylated in 21/35 HCCs (60%) and in 10/15 CCs (67%). LOH at 3p21.3 occurred in 8/35 (23%) HCCs and 3/15 (20%) CCs. The presence of hypermethylation was statistically associated with LOH of SEMA3B and correlated with downregulation of mRNA transcripts. SEMA3B transcripts increased upon treatment of HCC cell lines with the demethylation compound 5-aza-2-deoxycytidine. In conclusion, our data indicate that 2-hit gene silencing of SEMA3B through epigenetic changes and allele loss is a common and important event in the carcinogenesis of malignant liver tumors.

Aged↗

PubMed2006

Epigenetic inactivation of the SFRP genes is associated with drinking, smoking and HPV in head and neck squamous cell carcinoma.

The soluble frizzled receptor protein (SFRP) family encodes antagonists of the WNT pathway, and silencing of these genes, through promoter hypermethylation, leads to constitutive WNT signaling. In bladder cancers, hypermethylation of the SFRP genes occurs more often in current and former smokers and is a strong predictor of poor patient survival. Hence, we examined methylation of these genes in another tobacco-related epithelial cancer, head and neck squamous cell carcinoma (HNSCC), to determine if the pattern of tobacco exposure again predicts the epigenetic alteration of these genes. Using methylation-specific PCR, the prevalence of methylation of SFRP1, SFRP2, SFRP4 and SFRP5 was 35, 32, 35 and 29%, respectively among 350 HNSCC cases. Promoter methylation of SFRP1 occurred more often in both heavy (OR 3.5, 95% CI 0.9-13.7) and light drinkers (OR 3.7, 95% CI 1.0-14.3) compared to nondrinkers. SFRP4 promoter methylation, on the other hand, occurred at a higher prevalence in never smokers and former smokers than in current smokers, and also was independently associated with HPV16 viral DNA. A joint effects model of SFRP4 promoter methylation demonstrated that smoking status and HPV virus significantly interacted (p < 0.04) such that never smokers with HPV16 had an OR of SFRP4 methylation of 9.0 (95% CI 2.1-38.6). These results suggest that epigenetic alterations of the SFRP genes are highly prevalent in HNSCC, and that the clonal selection for these alterations is complex and may be related to the carcinogenic exposures that are known risk factors for this disease.

Aged↗

PubMed2006

Epigenetic silencing of multiple genes in primary CNS lymphoma.

Epigenetic silencing of functionally important genes is important in the development of malignancies and is a source of potential markers for molecular detection. Primary central nervous system lymphoma (PCNSL) is an increasingly common tumor that has not been extensively examined for changes in promoter region methylation. We examined 14 tumor suppressor genes in 25 cases of PCNSL using methylation-specific PCR. Methylation was observed in DAPK (84%), TSP1 (68%), CRBP1 (67%), p16(INK) (4a) (64%), p14(ARF) (59%), MGMT (52%), RARbeta2 (50%), TIMP3 (44%), TIMP2 (42%), p15(INK) (4b) (40%), p73 (28%), hMLH1 (12%), RB1 (8%) and GSTP1 (8%). Promoter methylation of p14(ARF), p16(INK) (4a) and MGMT was correlated with loss of expression by immunohistochemical staining. The methylation of many of these genes in PCNSL is similar to that reported in other high-grade B-cell lymphomas. All 25 cases of PCNSL had methylation of at least 2 genes. Methylation of DAPK, p16(INK) (4a) or MGMT was found in 96% of the tumors, suggesting simple marker strategies to detect circulating methylated DNA in serum that might facilitate early tumor detection. Our study provides insight into the epigenetic alterations in PCNSL and provides potential biomarkers of disease.

Adult↗

PubMed2005

In support of fatty acid synthase (FAS) as a metabolic oncogene: extracellular acidosis acts in an epigenetic fashion activating FAS gene expression in cancer cells.

Relatively little information exists on the ultimate molecular mechanisms by which the lipogenic enzyme Fatty Acid Synthase (FAS) is differentially overexpressed in a biologically aggressive subset of human malignancies. Since the microenvironment of solid tumors contains regions of poor oxygenation and high acidity, it has recently been suggested that cancer-associated FAS is a novel metabolic oncogene conferring a selective growth advantage upon stresses such as hypoxia and/or low pH. Here, we performed transient transfection studies with a 178-bp FAS promoter fragment harboring a complex Sterol Regulatory Element Binding Proteins (SREBP)-binding site to evaluate whether extracellular low pH and/or hypoxia may act in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in cancer cells. First, MCF-7 breast cancer cells cultured in acidosis (pH 6.5), but not under hypoxia or in the presence of hypoxia mimetics, demonstrated a more than two-fold increase in the transcriptional activity of FAS promoter-reporter constructs compared with control cells grown under standard culture conditions (pH 7.4). Second, the up-regulatory effect of extracellular acidosis on the transcriptional activation of FAS gene was not observed when the FAS promoter was truncated at the SREBP-binding site. Third, MCF-7 cells engineered to overexpress the Her-2/neu (erbB-2) oncogene exhibited a SREBP-dependent activation of the FAS promoter-reporter construct up to three-fold higher than that found in wild-type MCF-7 cells, while extracellular acidosis resulted only in a marginal increase of Her-2/neu-promoted activation of FAS gene. This study reveals for the first time that extracellular acidosis can work in an epigenetic fashion by up-regulating the transcriptional expression of FAS gene in breast cancer cells, a stimulatory effect that is equally mimicked by well-characterized oncogenic stimuli such as Her-2/neu. These findings, altogether, support the "metabolic oncogene" theory for FAS overexpression in cancer cells.

Acidosis↗

PubMed2005

Genetic and epigenetic aspects of bladder cancer.

Transitional cell carcinoma of the urinary bladder has a diverse collection of biologic and functional characteristics. This is reflected in differing clinical courses. The diagnosis of bladder cancer is based on the information provided by cystoscopy, the gold standard in combination with urinary cytology findings. Many tumor markers have been evaluated for detecting and monitoring the disease in serum, bladder washes, and urinary specimens. However, none of these biomarkers reported to date has shown sufficient sensitivity and specificity for the detection of the whole spectrum of bladder cancer diseases in routine clinical practice. The limited value of established prognostic markers requires the analysis of new molecular parameters of interest in predicting the prognosis of bladder cancer patients; in particular, the high-risk patient groups at risk of progression and recurrence. Over the past decade, there has been major progress elucidating of the molecular genetic and epigenetic changes leading to the development of transitional cell carcinoma. This review focuses on the recent advances of genetic and epigenetic aspects in bladder cancer, and emphasizes how molecular biology would be likely to affect the future therapies.

Biomarkers, Tumor↗

PubMed2006

Antitumor efficacy of DNA vaccination to the epigenetically acting tumor promoting transcription factor BORIS and CD80 molecular adjuvant.

Cancer testis (CT) antigens are promising candidates for tumor vaccines due to their immunogenicity and tissue-restricted expression. Recently, we identified a novel cancer testis gene, BORIS, whose expression is restricted to male testis after puberty and is strictly absent in non-malignant female tissue. BORIS encodes a DNA-binding protein that shares 11 zing finger (ZF) with transcription factor CTCF and differs at the N- and C-termini. CTCF has been implicated in epigenetic regulation of imprinting, X chromosome inactivation, repression, and activation of cancer testis antigens. BORIS expression has been documented in cancers of diverse histological origin, including, but not limited to breast, prostate, ovary, gastric, liver, endometrial, glia, colon, and esophagus. Interestingly, BORIS induces demethylation and subsequent expression of many cancer-testis genes, including MAGE-A1 and NY-ESO-1, indicating that it is expressed very early in malignancy and might be an attractive candidate for immunotherapy. In this study we tested BORIS as a vaccine in a very aggressive, highly metastatic, and poorly immunogenic murine model of mammary carcinoma. Immunizations with a DNA encoding the mutant form of murine BORIS antigen (pmBORIS lacking DNA-binding function) significantly prolonged survival, and inhibited tumor growth in BALB/c mice inoculated with 4T1 cells. Priming with pmBORIS mixed with molecular adjuvant and boosting with adenoviral vector expressing mBORIS was generally more effective, suggesting that the vaccination protocol could be further optimized. This is the first report demonstrating the feasibility of vaccination with a cancer associated epigenetic regulator for the induction of tumor inhibition.

Adjuvants, Immunologic↗

PubMed2007

Epigenetic modifiers promote efficient generation of neural-like cells from bone marrow-derived mesenchymal cells grown in neural environment.

Understanding mechanisms that govern cell fate decisions will lead to developing techniques for induction of adult stem cell differentiation to desired cell outcomes and, thus, production of an autologos source of cells for regenerative medicine. Recently, we demonstrated that stem cells derived from adult central nervous system or bone marrow grown with other cell lineages or with more undifferentiated cells sometimes take on those characteristics. This indicates that manipulating extracellular factors may be sufficient to alter some developmental restrictions regulated by the epigenetic system. In this study, using pharmacological agents that interfere with the main components of the epigenetic program such as DNA methylation and histone deacetylation, we induce high-level expression of embryonic and neural stem cell (NSC) marker Sox2 in bone marrow-derived mesenchymal stem cells (MSCs). Exposure of these modified cells to a neural environment via juxtacrine and paracrine interactions promote efficient generation of neural stem-like cells as well as cells with neuronal and glial characteristics. We concluded that the manipulation strategy used in this study can be a useful method for efficient production of NSC-like cells from MSCs.

Animals↗

PubMedDate not supplied

Insulin/insulin-like growth factor I and other epigenetic modulators of myelin basic protein expression in isolated oligodendrocyte progenitor cells.

The expression of myelin basic protein by the oligodendrocyte is an integral event in the maturation of central nervous system function. Although much is known concerning the various myelin basic protein species, their temporal expression, and processing of RNA transcripts, little is known about the epigenetic factors responsible for the regulation of myelin basic protein (MBP) expression. In this study, we present evidence that insulin/insulin-like growth factor-I can increase the levels of MBP protein in isolated oligodendrocyte progenitor cells cultured in a serumless, chemically defined medium (ODM). Insulin was found to increase MBP protein in a dose-responsive manner, reaching a maximal level at 72 hr of exposure. Both insulin-like growth factor-I (IGF-I) and insulin were demonstrated to have no effect on MBP RNA levels. These data indicate that insulin/IGF-I increased MBP protein levels at a level distal to transcription The dose response of insulin action suggests that it may have a MBP regulatory function, distinct from IGF-I. When added individually, the other supplements of ODM, transferrin (500 ng/ml), and basic fibroblast growth factor (5 ng/ml) had no effect on MBP expression. However, when all three components were combined, a synergistic effect resulting in increased MBP protein and total RNA levels was found. The phorbol ester 12-O-tetradecanoyl phorbol acetate was found to reduce intracellular MBP RNA levels. The cAMP analogue/dibutyryl cAMP had contrasting effects on MBP RNA levels; no effect occurred in cultures grown in fetal calf serum, but a reduction in RNA levels was found in cultures grown in ODM. These data suggest that only a select range of extrinsic factors may be involved in MBP regulation, and depending on the environmental milieu, epigenetic agents may modulate gene activity differently.

Animals↗