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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of an oncogenic v-Ha-ras gene on the expression of TGF-beta and TGF-alpha by mouse keratinocytes and derived tumors has been investigated. Normal mouse keratinocytes cultured as basal cells in 0.05 mM Ca2+ secreted low levels of TGF-beta 2 peptide, and this increased markedly following culture in 1.4 mM Ca2+, retinoic acid, or phorbol esters. In contrast, introduction of a v-Ha-ras gene into normal keratinocytes increased basal expression and secretion of TGF-beta 1 (rather than TGF-beta 2) in response to all three agents. The selective secretion of TGF-beta 1 in v-Ha-ras keratinocytes in response to 1.4 mM Ca2+ occurred even though the four TGF-beta 2 transcripts were induced and the TGF-beta 1 transcript decreased, suggesting that the activated v-Ha-ras gene product regulates expression of the TGF-beta isoforms at the posttranscriptional level. Immunohistochemical analysis of papillomas formed following skin grafting of v-Ha-ras keratinocytes onto nude mice indicated that TGF-beta 1 was abundant in the basal and spinous layers, while there was no expression of TGF-beta 1 in normal skin. In contrast, both normal and neoplastic tissues expressed TGF-beta 2 and TGF-beta 3 in the granular layers. Furthermore, TGF-alpha mRNA expression was also elevated fivefold in cultured v-Ha-ras keratinocytes, and TGF-alpha protein was overexpressed in the grafted papillomas, but there was no detectable expression in normal skin. Elevated expression of both TGF-beta 1 and TGF-alpha in the basal and spinous layers of benign tumors may be important for the high proliferation rate in these tumors as well as for increased proliferation in the suprabasal layer.
Mol Carcinog 1991
PMID:Altered regulation of TGF-beta 1 and TGF-alpha in primary keratinocytes and papillomas expressing v-Ha-ras. 206 27

1. Neuroblastoma (NB) is an unusual neuroectodermal tumor showing a high degree of spontaneous regression. NB cells can be induced to differentiate in vitro by various agents. Cell differentiation results in morphological changes characteristic of the mature neuronal phenotype, including outgrowth of neurite-like structures with several interconnections. 2. Recent experiments indicate that morphological differentiation of NB cells is associated with changes in expression of N-myc, c-myc, and c-myb oncogenes and synthesis of neurofilament proteins. However, little is known about the transcription of neurofilament genes during differentiation. 3. We have analyzed the expression of both the N-myc oncogene and mid-size neurofilament (NF) genes in the LAN-1 human NB cell line, cultured in the presence of retinoic acid (RA). Continuous treatment with RA induced morphological differentiation within 5-6 days. The transcription of N-myc was down-modulated within 24 hr of the initial exposure to RA. The mid-size NF mRNA was increased at this time. The expression of N-myc was not modified in serum-deprived LAN-1 cells, indicating that N-myc transcription is unaffected by the arrest of the cells in the G1 phase. 4. We conclude that new synthesis of mid-size NF mRNA and a decrease in N-myc transcription precede de novo formation of neurite-like processes and morphological cell differentiation of neuroblastoma cells.
Cell Mol Neurobiol 1990 Sep
PMID:Different regulation of mid-size neurofilament and N-myc mRNA expression during neuroblastoma cell differentiation induced by retinoic acid. 212 47

Retinoic acid (RA) receptor alpha (RAR alpha) and RAR gamma steady-state mRNA levels remained relatively constant over time after the addition of RA to F9 teratocarcinoma stem cells. In contrast, the steady-state RAR beta mRNA level started to increase within 12 h after the addition of RA and reached a 20-fold-higher level by 48 h. This RA-associated RAR beta mRNA increase was not prevented by protein synthesis inhibitors but was prevented by the addition of cyclic AMP analogs. In the presence of RA, cyclic AMP analogs also greatly reduced the RAR alpha and RAR gamma mRNA levels, even though cyclic AMP analogs alone did not alter these mRNA levels. The addition of either RA or RA plus cyclic AMP analogs did not result in changes in the three RAR mRNA half-lives. These results suggest that agents which elevate the internal cyclic AMP concentration may also affect the cellular response to RA by altering the expression of the RARs.
Mol Cell Biol 1990 Jan
PMID:Cyclic AMP analogs and retinoic acid influence the expression of retinoic acid receptor alpha, beta, and gamma mRNAs in F9 teratocarcinoma cells. 215 65

Retinoic acid is known to have profound effects on developmental processes. It has been implicated as a putative morphogen in the developing chick limb bud and regenerating amphibian limb blastema and has been demonstrated to have powerful teratogenic effects in mammals, including humans. Recently, three specific retinoic acid receptors (RARs), RAR alpha, -beta, and -gamma, were identified and shown to be members of the steroid receptor superfamily. We report the identification of a novel RAR gamma isoform, mRAR gamma B, which differs from the previously described mouse RAR gamma at its amino terminus. In addition, we show that both RAR gamma isoforms are expressed maximally at midgestation in structures known to be affected adversely by retinoic acid administration to pregnant mice. Multiple RAR isoforms, each of which may play a unique or combinatorial role as a regulator of mammalian development, are thus expressed in the mouse embryo.
Mol Cell Biol 1990 May
PMID:Identification of a novel isoform of the retinoic acid receptor gamma expressed in the mouse embryo. 215 70

c-fos was studied in F9 cells to determine whether changes in its expression are an early and/or obligatory event in retinoic acid-induced F9 cell differentiation. Induction of c-fos transcripts was not observed at times early or late during retinoic acid-promoted differentiation, but a decrease in c-myc mRNA was noted as early as 1 h after retinoic acid dosing. Induction of a rapid and transient change in c-fos expression in F9 cells was observed only in response to serum stimulation. Therefore, although expression of c-fos may be involved in the cellular growth and proliferation of F9 cells, as indicated by the response to serum, an increase in c-fos is not required for retinoic acid-induced differentiation.
Mol Cell Endocrinol 1990 May 28
PMID:Enhanced expression of c-fos is not obligatory for retinoic acid-induced F9 cell differentiation. 216 31

Human fetal brain expresses high levels of a polypeptide identified by protein biochemistry and molecular cloning as thymosin beta 10. Within the first 18 months after birth, the thymosin beta 10 content of human brain falls to undetectable levels. In order to establish the molecular basis of this process we screened a number of human tumor cell lines derived from the nervous system for the presence of thymosin beta 10. All of the cell line expressed authentic thymosin beta 10. However, in the HTB-10 neuroblastoma, retinoic acid caused a reduction in the level of thymosin beta 10. This effect of the retinoid was conditional upon its continual presence in the tissue culture medium and was not evident in the other cell lines examined. These results suggest that the thymosin beta 10 gene may be a target for retinoids in the developing nervous system.
Brain Res Mol Brain Res 1990 Jul
PMID:Thymosin beta 10 levels in developing human brain and its regulation by retinoic acid in the HTB-10 neuroblastoma. 216 66

Chronic hepatitis B virus (HBV) infection is etiologically related to human hepatocellular carcinoma (HCC). Most HCCs contain integrated HBV DNA in the liver cellular DNA, suggesting that the integration may be involved in carcinogenesis. From a comparison of a single HBV integration site present in a hepatoma with the corresponding unoccupied site in the non-tumourous tissue of the same liver, we have shown that HBV DNA inserted in a putative cellular exon with striking similarity to the DNA-binding domain of the thyroid/steroid hormone receptors. The corresponding cDNA has been isolated (hap gene) and shown to encode the retinoic acid receptor. In the original patient, integration took place so that the first codons of the viral surface protein gene became fused in frame with most of the hap gene. Because retinoic acid is known to regulate the transcription of target genes crucial for cellular growth and differentiation, it is most probable that consequent to the HBV insertion, hap, usually transcribed at a very low level in normal hepatocytes, became inappropriately expressed as an altered chimaeric retinoic acid receptor, thus contributing to the cell transformation. These results strongly support the possibility that HBV may play a direct role in liver carcinogenesis by insertional mutagenesis.
Mol Biol Med 1990 Jun
PMID:Hepatitis B virus as an insertional mutagene in a human hepatocellular carcinoma. 217 Aug 9

The induced differentiation of F9 cells by retinoic acid (RA) and cyclic AMP (cAMP) activated transcription of the tissue plasminogen activator (t-PA) gene. This differentiation-responsive regulation of the t-PA promoter was also observed in transient assays. Multiple sequence elements within 243 bp of t-PA DNA contributed to the high level of transcription in retinoic acid- and cyclic AMP-differentiated cells. To investigate the factors involved in controlling t-PA transcription upon differentiation, we used F9 cell extracts to examine proteins that bind two proximal promoter elements. These elements (boxes 4 and 5) are homologous to GC boxes that are known binding sites for transcription factor Sp1. Mobility shift assays in the presence and absence of anti-Sp1 antibodies demonstrated that the proteins which bound to this region were immunologically related to human Sp1. The proteins also had a DNA-binding specificity similar to that of a truncated form of Sp1. Mutations of the GC motif within boxes 4 and 5 that interfered with Sp1 binding reduced in parallel the binding of the F9 cellular factors and lowered transcription in vitro as well as in vivo. Although this proximal region of the t-PA promoter was active in vivo only in differentiated cells, the Sp1-like binding proteins were present in equal concentrations and had similar properties in extracts of both stem and differentiated cells. These data suggest that other cellular elements participate with this Sp1-like factor in controlling differentiation-specific expression.
Mol Cell Biol 1990 Nov
PMID:Transcription factor Sp1 is important for retinoic acid-induced expression of the tissue plasminogen activator gene during F9 teratocarcinoma cell differentiation. 217 88

A cDNA clone derived from a human hepatocellular carcinoma has been isolated on the basis of homology to the alpha human retinoic acid receptor (RAR alpha) gene. Expression of this cDNA produces a high affinity nuclear binding protein for retinoic acid. The product of this clone when expressed in transfected cells is able to activate transcription of a reporter plasmid through specific DNA sequences in response to the addition of retinoic acid to the medium. Dose-dependent profiles upon trans-activation of the reporter indicate that apparent sensitivity to retinoic acid of this protein is approximately 10-fold higher than that of human RAR alpha and is comparable to that of the second human RAR, RAR beta. This gene has been mapped to human chromosome 12, which is distinct from those coding for either alpha or beta RAR, and thus encodes a third human RAR.
Mol Endocrinol 1990 Jun
PMID:A functional retinoic acid receptor encoded by the gene on human chromosome 12. 217 93

Pluripotential embryonal carcinoma cells such as those of the P19 line differentiate when exposed to retinoic acid (RA). The RAC65 cell line is a mutant clone of P19 cells selected to be RA nonresponsive. RAC65 cells carry a rearrangement affecting one of the genes encoding a nuclear retinoic acid receptor (RAR alpha). The mutant gene encodes a protein, RAR alpha', that has lost its 70 C-terminal amino acids, thus truncating the RA-binding domain. The RAR alpha' was found to be a dominant repressor of transcription from an RA-responsive target gene; however, expression of RAR alpha' was insufficient to confer RA nonresponsiveness, suggesting that RAC65 cells carry an additional mutation(s) affecting RA-induced genes.
Mol Cell Biol 1990 Dec
PMID:A dominant negative mutation of the alpha retinoic acid receptor gene in a retinoic acid-nonresponsive embryonal carcinoma cell. 217 8


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