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In this study, we extended the previous observations of a growth hormone-regulated sex difference in hepatic c-myc expression in the resistant hepatocyte model during the selection/promotion phase, when sex differences in growth rate of enzyme-altered foci are first identified, to studies of the regulation of this gene during later stages of hepatocarcinogenesis. The expression of the c-myc gene was studied in preneoplastic nodules, hepatocellular carcinomas, and the corresponding surrounding livers of male and female Wistar rats treated according to the resistant hepatocyte model. In males, nodules isolated 8 and 11-12 mo after initiation and hepatocellular carcinomas exhibited a 2.5- to threefold higher c-myc expression than the surrounding liver. In females, no increase in c-myc expression was observed in nodules 8 mo after initiation, while nodules isolated after 11-14 mo and tumors showed a twofold and threefold increase, respectively, when compared with the surrounding tissue. Increased transcription of the c-myc gene was observed in nuclei from male nodules isolated 11 mo after initiation compared with nuclei from the surrounding liver. The difference in transcription between male nodules and surrounding tissue is similar for the first and second exon of the gene. Continuous infusion of growth hormone to nodule-bearing male rats 8 and 11 mo after initiation decreased c-myc expression in the surrounding tissue and downregulated the expression in 8-mo nodules to the level in the surrounding liver. No significant decrease in response to growth hormone treatment was seen in 11-mo nodules. In hypophysectomized nodule-bearing males, nodular c-myc remained upregulated. Taken together, the data showed that the sex difference in c-myc expression was maintained during a large part of the progression period. Furthermore, the loss of growth hormone regulation of the c-myc gene in advanced male nodules indicated an escape from normal regulatory mechanisms during progression. These findings might reflect a role for the c-myc gene in sex-differentiated rat liver carcinogenesis.
Mol Carcinog 1991
PMID:Role of growth hormone in the regulation of the c-myc gene during progression of sex-differentiated rat liver carcinogenesis in the resistant hepatocyte model. 191 Apr 82

The autocrine, paracrine, or systemic growth factors responsible for fetal lung cell growth are not completely defined. The progression-type insulin-like growth factors and epidermal growth factor, or transforming growth factor-alpha acting through the epidermal growth factor receptor, appear to act on the developing lung epithelium. The competence factors that facilitate the actions of progression factors during lung growth are unknown. Fetal rat lung cells in vitro synthesize a platelet-derived growth factor (PDGF)-like polypeptide, which we have hypothesized may play a paracrine role in normal lung development. Slot blot and Northern blot analyses of fetal rat lung mRNA have been used to determine if there is a relationship between expression of message for PDGF-A or PDGF-B chains, or their cognate receptors, and periods of maximal growth during late fetal rat lung development. Whole lung mRNA was extracted on 18, 19, 20, 21, and 22 days of gestation (term = 22 days). The peak of DNA synthesis, as assessed by expression of message for DNA polymerase alpha, histone 3, and the proto-oncogenes c-fos and c-myc, which are stimulated by binding of growth factors including PDGF, occurred during the canalicular stage of lung development on days 19 and 20 of gestation. Expression of message for PDGF-A and PDGF-B chains was low during the pseudoglandular stage on day 18, peaked during the canalicular stage on days 19 and 20, then fell again during the saccular stage at days 21 and 22 of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1991 Oct
PMID:Platelet-derived growth factor and growth-related genes in rat lung. I. Developmental expression. 191 Aug 22

Transgenic animals provide a model system to elucidate the role of specific proteins in development. This model is now being used increasingly in the cardiovascular system to study cardiac growth and differentiation. During cardiac myocyte development a transition occurs from hyperplastic to hypertrophic growth. In the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc functions to regulate myocyte proliferation and/or differentiation, we examined the in vivo effect of increasing c-myc expression during fetal development and of preventing the decrease in c-myc mRNA expression that normally occurs during myocyte development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. Increased c-myc mRNA expression is associated with both atrial and ventricular enlargement in the transgenic mice. This increase in cardiac mass is secondary to myocyte hyperplasia, with the transgenic hearts containing greater than twice as many myocytes as nontransgenic hearts. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth, and suggest a regulatory role for the c-myc protooncogene in cardiac myogenesis.
Mol Cell Biochem
PMID:Transgenic animals as a tool for studying the effect of the c-myc proto-oncogene on cardiac development. 192 94

The growth-suppressive function of the retinoblastoma susceptibility gene product, RB, has been implicated in the mediation of growth inhibition and negative regulation of certain proliferation related genes by transforming growth factor-beta 1 (TGF-beta 1). Early gene responses to TGF-beta 1 were examined in order to determine their dependence on the cell cycle and on the growth-suppressive function of RB. TGF-beta 1, which rapidly elevates the steady-state level of junB and PAI-1 mRNAs and decreases that of c-myc mRNA, induces these responses in S-phase populations of Mv1Lu lung epithelial cells containing RB in a phosphorylated state. Since in this state RB is presumed to lack growth-suppressive activity, the response to TGF-beta 1 was also examined in DU145 human prostate carcinoma cells whose mutant RB product lacks growth-suppressive function. In these cells, TGF-beta 1 also decreases c-myc expression at the transcription initiation level. These results suggests that the c-myc, junB, and PAI-1 responses to TGF-beta 1 are not restricted to the G1 phase of the cell cycle and that down-regulation of c-myc expression by TGF-beta 1 can occur through a mechanism independent from the growth-suppressive function of RB.
Mol Cell Biol 1991 Oct
PMID:Early gene responses to transforming growth factor-beta in cells lacking growth-suppressive RB function. 192 28

A DNA-binding factor with properties of NF-kappa B and another similar activity are rapidly induced when growth-arrested BALB/c 3T3 cells are stimulated with serum growth factors. Induction of these DNA-binding activities is not inhibited by pretreatment of quiescent cells with the protein synthesis inhibitor cycloheximide. Interestingly, the major NF-kappa B-like activity is not detected in nuclear extracts of proliferating cells, and thus its expression appears to be limited to the G0-to-G1 transition in 3T3 cells. These DNA-binding activities bind many of the expected NF-kappa B target sequences, including elements in the class I major histocompatibility complex and human immunodeficiency virus enhancers, as well as a recently identified NF-kappa B binding site upstream of the c-myc gene. Furthermore, both the class I major histocompatibility complex and c-myc NF-kappa B binding sites confer inducibility on a minimal promoter in 3T3 cells stimulated with serum growth factors. The results demonstrate that NF-kappa B-like activities are immediate-early response proteins in 3T3 cells and suggest a role for these factors in the G0-to-G1 transition.
Mol Cell Biol 1991 Oct
PMID:Induction of NF-kappa B DNA-binding activity during the G0-to-G1 transition in mouse fibroblasts. 192 27

This study documents a biphasic change in the rate of cell cycle progression and proliferation of T-47D human breast cancer cells treated with synthetic progestins, consisting of an initial transient acceleration in transit through G1, followed by cell cycle arrest and growth inhibition. Both components of the response were mediated via the progesterone receptor. The data are consistent with a model in which the action of progestins is to accelerate cells already progressing through G1, which are then arrested early in G1 after completing a round of replication, as are cells initially in other phases of the cell cycle. Such acceleration implies that progestins act on genes or gene products which are rate limiting for cell cycle progression. Increased production of epidermal growth factor and transforming growth factor alpha, putative autocrine growth factors in breast cancer cells, does not appear to account for the initial response to progestins, since although the mRNA abundance for these growth factors is rapidly induced by progestins, cells treated with epidermal growth factor or transforming growth factor alpha did not enter S phase until 5 to 6 h later than those stimulated by progestin. The proto-oncogenes c-fos and c-myc were rapidly but transiently induced by progestin treatment, paralleling the well-known response of these genes to mitogenic signals in other cell types. The progestin antagonist RU 486 inhibited progestin regulation of both cell cycle progression and c-myc expression, suggesting that this proto-oncogene may participate in growth modulation by progestins.
Mol Cell Biol 1991 Oct
PMID:Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor alpha, epidermal growth factor receptor, c-fos, and c-myc genes. 192 31

The role of local sequence information in establishing the chromatin structure of the human c-myc upstream region (MUR) was investigated. Adeno-associated virus (AAV)-mediated gene transduction was used to introduce an additional unrearranged copy of the 2.4 kb HindIII-XhoI fragment of the MUR into a novel location in the genome in each of two cloned HeLa cell lines. The AAV-based rep- cap- viral vector SKMA used to transduce the MUR retained only 1.4 kb (24%) of the AAV genome and could accommodate inserts as large as 2.4 kb. SKMA was capable of infecting HeLa cells and integrating into the host genome at single copy number. Integration may have occurred at a preferred site in the HeLa genome, but this site was apparently distinct from the previously identified preferred AAV integration site on human chromosome 19. Indirect end-labelling was used to map DNase I and micrococcal nuclease (MNase) cleavage sites over the transduced c-myc sequences and the endogenous c-myc loci in infected HeLa cells. A similarly ordered chromatin domain, extending 5' from c-myc promoter P0, was found to exist at the transduced c-myc locus in each clone. The position and relative sensitivity of 13 MNase cleavage sites and five DNase I hypersensitive sites, originally identified at the endogenous MUR in non-transduced cells, were shown to be conserved when this DNA was moved to a new chromosome site. A conserved DNase I hypersensitive site also was mapped to the region between the left AAV terminal repeat and AAV promoter P5. These results suggest that the information required to establish the particular chromatin structure of the MUR resides within the local DNA sequence of that region.
J Mol Biol 1991 Nov 05
PMID:Conserved chromatin structure in c-myc 5'flanking DNA after viral transduction. 194 68

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) receptor concentration, cell proliferation, and the steady-state level of c-myc mRNA were examined in the C3H/10T1/2 mouse embryo fibroblasts, before and after exposing the cells to 1,25-(OH)2D3. The non-transformed, logarithmically growing C3H/10T1/2 Cl 8 cells contained a high concentration of 1,25-(OH)2D3 receptor (164 fmol/mg of protein). An up-regulation of the 1,25-(OH)2D3 receptor and a potent inhibition of cell growth were observed by exposing the cells to 10 nM 1,25-(OH)2D3. The concentration of 1,25-(OH)2D3 receptor in the two chemically transformed, tumorigenic cell lines. C3H/10T1/2 Cl 16 and C3H/10T1/2 TPA 482, was 218 and 63 fmol/mg of protein, respectively. In the two transformed cell lines, 10 nM 1,25-(OH)2D3 had only negligible effect on cell growth. In the Cl 16 cells, an up-regulation of the 1,25-(OH)2D3 receptor was demonstrated, but only a weak up-regulation was found in the TPA 482 cells by the 1,25-(OH)2D3 treatment. No major changes were found in c-myc mRNA levels by the 1,25-(OH)2D3 treatment. Despite inhibition of cell growth, the steady-state level of c-myc mRNA was slightly induced (35%, mean) in the Cl 8 cells compared to control cells. In the transformed cells, no consistent change of the c-myc level was found. In contrast to earlier reports, we did not find any correlation between the 1,25-(OH)2D3 receptor and c-myc level, nor did we find any decrease of c-myc mRNA by 1,25-(OH)2D3 treatment in the C3H/10T1/2 fibroblasts.
Mol Cell Endocrinol 1990 Dec 21
PMID:Effect of 1,25-(OH)2-vitamin D3 on growth, homologous receptor and c-myc regulation in C3H/10T1/2 cells. 196 47

Two extraction methods for the isolation of DNA from formalin-fixed, paraffin-embedded tissue samples from colonic carcinomas were compared. The processed DNAs were compared with DNAs from fresh specimens of the same tumors. The two extraction methods gave similar results. Formalin-fixation and paraffin-embedding irreversibly denatured DNA and consequently decreased the extraction yield and interfered with the quantitative measurement of DNA. Southern blot and dot blot analysis of processed and native DNA was performed using a c-myc and an actin probe. The results show that for Southern analysis processed DNA can be used but, due to the generation of random breaks, the restriction fragments have to be small. Furthermore, the fixation-induced crosslinking of DNA appears to hamper hybridization. For these reasons processed DNA can be analyzed better by dot blot rather than Southern blot hybridization.
Virchows Arch B Cell Pathol Incl Mol Pathol 1990
PMID:Southern and dot blot analysis of DNA from formalin-fixed, paraffin-embedded tissue samples from colonic carcinomas. 197 Nov 30

Thirty colorectal carcinomas, 1 adenoma of the colon, 1 case of Crohn's disease and 13 specimens of non-neoplastic colorectal mucosa were examined for qualitative and quantitative expression of the c-myc and c-fos protooncogenes. These genes encode nuclear proteins, which are both believed to regulate gene transcription. Oncogene expression was evaluated at the mRNA level by in situ hybridization and Northern blot analysis. Densitometric analysis of the specific bands on Northern blots revealed a highly significant overexpression of c-myc mRNA in colorectal carcinomas compared with non-neoplastic tissue (p less than 0.001). Furthermore, increased expression of c-myc mRNA was found in moderately and poorly differentiated carcinomas compared with well differentiated ones. In contrast to c-myc, c-fos mRNA expression was significantly lower in carcinomas than in non neoplastic tissue (p less than 0.02). Neither, c-myc nor c-fos mRNA levels showed a clear-cut correlation with tumor stage. We conclude that c-myc mRNA overexpression plays an important role in the progression of colorectal carcinomas. In contrast enhanced c-fos mRNA expression may be related to cell differentiation, both in tumors and non-neoplastic tissue.
Virchows Arch B Cell Pathol Incl Mol Pathol 1990
PMID:Expression of c-myc and c-fos mRNA in colorectal carcinoma in man. 198 Jul 63


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