Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The retinoblastoma protein interacts with a number of cellular proteins to form complexes which are probably crucial for its normal physiological function. To identify these proteins, we isolated nine distinct clones by direct screening of cDNA expression libraries using purified RB protein as a probe. One of these clones, Ap12, is expressed predominantly at the G1-S boundary and in the S phase of the cell cycle. The nucleotide sequence of Ap12 has features characteristic of transcription factors. The C-terminal region binds to unphosphorylated RB in regions similar to those to which T antigen binds and contains a transactivation domain. A region containing a potential leucine zipper flanked by basic residues is able to bind an E2F recognition sequence specifically. Expression of Ap12 in mammalian cells significantly enhances E2F-dependent transcriptional activity. These results suggest that Ap12 encodes a protein with properties known to be characteristic of transcription factor E2F.
Mol Cell Biol 1992 Dec
PMID:Molecular cloning of cellular genes encoding retinoblastoma-associated proteins: identification of a gene with properties of the transcription factor E2F. 144 92

Four human lung adenocarcinoma cell lines were established in serum-free F12 medium supplemented with insulin, transferrin, hydrocortisone, cholera toxin, selenium, epidermal growth factor, bovine hypothalamic extract, and retinoic acid. Histochemical analyses with periodic acid-Schiff with and without diastase treatment (PAS-D technique) and immunocytochemistry with a mucin-specific monoclonal antibody demonstrated that three of the cell lines (CL2, CL3, and NCL2) were capable of mucin production. Biochemical characterizations of mucin produced by adenocarcinoma cells were focused on one of the cell lines, CL2 cells, which showed the most prominent reactivity with mucin-specific monoclonal antibody. Biochemical analysis using the mucin precursors [3H]glucosamine and [14C]serine indicated that CL2 cells can synthesize high-molecular-weight (M(r) greater than 200 kD) glycoprotein molecules that can be immunoprecipitated by this mucin-specific monoclonal antibody. The high-molecular-weight glycoproteins isolated from CL2 cells specifically reacted with mucin-specific monoclonal antibody by Western blot analysis, and composition analyses showed high levels of serine and threonine and a low level of aromatic amino acids, which are similar to human airway mucin. These observations suggest that lung adenocarcinoma CL2 cells cultured in this serum-free medium can retain function of airway mucin synthesis. Cell kinetic studies of these four cell lines showed that the cell line (CL1) without the mucin differentiation had a higher proliferative index and a shorter population doubling time as compared with the other three cell lines (CL2, CL3, and NCL2) with mucin differentiation. Examination of the retinoblastoma protein expressions in these adenocarcinoma cell lines revealed a phosphorylated pattern that correlated inversely with the mucin synthesis status of these cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Aug
PMID:Characterization of the mucin differentiation in human lung adenocarcinoma cell lines. 149 5

One of the major E1A-associated cellular proteins is a 300-kDa product (p300) that binds to the N-terminal region of the E1A products. The p300 binding site is distinct from sequences involved in binding the retinoblastoma product and other E1A-associated cellular products such as p60-cyclin A and p107. p300 binding to E1A is linked genetically to the enhancer repression function of E1A and the other E1A-mediated gene-regulating functions as well as to the transforming functions of E1A. However, the biochemical properties of p300 have not yet been characterized. We report here that p300 has an intrinsic DNA-binding activity and shows a preferential affinity for specific DNA sequences. The sequences selectively bound by p300 are related to those of a series of enhancer elements that are recognized by NF-kappa B. The direct physical interaction of p300 with enhancer elements provides a biochemical basis for the genetic evidence linking the E1A-mediated enhancer repression function with the p300-binding activity of E1A.
Mol Cell Biol 1992 Jun
PMID:DNA-binding properties of the E1A-associated 300-kilodalton protein. 153 43

The level of fibronectin (FN) gene transcription in resting rat 3Y1 cells is very high but decreases steeply after growth stimulation by serum or by the induction of E1A expression. To study the mechanism of this E1A-mediated down-regulation, the 5' flanking regions of the FN gene with various deletions and substitutions were fused to the Escherichia coli chloramphenicol acetyltransferase (CAT) gene and introduced into resting 3Y1 cells with E1A expression plasmids. The results indicate that the G10 stretch located from nucleotide position -239 to -230 and two GC boxes from position -105 to -95 and position -54 to -44 are the primary E1A-responsive elements for repression of the FN gene. Two GC boxes also contain a G10 stretch that is interrupted by the presence of an internal C residue. These sequences overlap with the Sp1 motif GGGCGG. Substitution of the sequence GGGG with ATCC or CTTA in these G-rich sequences, leaving the Sp1 motif intact, completely abolished the E1A sensitivity of the promoter. Analysis of the E1A domains by using various E1A deletion mutants indicated that the domain for binding to the retinoblastoma susceptibility gene product (RB) is essential for efficient repression. These results suggest that the gene encoding a negative factor(s) binding to the three G-rich sequences in the FN promoter is repressed by RB in resting 3Y1 cells and derepressed by expression of E1A.
Mol Cell Biol 1992 Jun
PMID:E1A-responsive elements for repression of rat fibronectin gene transcription. 153 44

The protein product (pRB) of the retinoblastoma susceptibility gene functions as a negative regulator of cell proliferation, and its activity appears to be modulated by phosphorylation. Using a new panel of anti-human pRB monoclonal antibodies, we have investigated the biochemical properties of this protein. These antibodies have allowed us to detect a pRB-associated kinase that has been identified as the cell cycle-regulating kinase p34cdc2 or a closely related enzyme. Since this associated kinase phosphorylates pRB at most of the sites used in vivo, these results suggest that this kinase is one of the major regulators of pRB. The associated kinase activity follows the pattern of phosphorylation seen for pRB in vivo. The associated kinase activity is not seen in the G1 phase but appears in the S phase, and the levels continue to increase throughout the remainder of the cell cycle.
Mol Cell Biol 1992 Mar
PMID:The retinoblastoma protein physically associates with the human cdc2 kinase. 154 27

Twenty-five mouse lung tumors induced by a single urethan treatment in female A/J, BALB/c, and (A/J x C3H/He)F1 (AC3) mice were analyzed for the presence of mutations at codon 61 of the Ki-ras gene and for the expression of the surfactant protein A (SP-A), retinoblastoma (Rb), growth arrest-specific-3 (gas-3), p53, c-myc, and thymidylate synthase (TS) genes. Ki-ras codon 61 mutations were detected in 22 of 25 tumor samples without differences among strains. In comparison with normal lungs, all the tumors showed increased SP-A mRNA levels, indicating their derivation from alveolar type II pneumocytes or Clara cells. Rb and gas-3 transcripts were instead found in all tumors at about tenfold and about 20-fold reduced levels, respectively. No apparent structural alterations or loss of heterozygosity at the Rb locus was detected in any tumors. The p53 mRNA was observed without variation in quantity or size in lung tumors and normal tissue. A threefold to fivefold c-myc overexpression was observed, without amplification of the gene. TS expression was only slightly increased, indicating no great differences in cell proliferation between lung tumors and normal tissue. Our data suggest that the pathogenesis of urethan-induced lung tumors in mice involves specific and recurrent molecular alterations (Ki-ras mutations, decrease of Rb and gas-3 expression, and increase of c-myc expression) that could represent different steps in lung carcinogenesis.
Mol Carcinog 1992
PMID:Multiple molecular alterations in mouse lung tumors. 155 14

We have demonstrated that the retinoblastoma gene product (Rb) can positively regulate transcription from the fourth promoter of the insulinlike growth factor II gene. Two copies of a motif (the retinoblastoma control element) similar to that found in the human c-fos, transforming growth factor beta 1, and c-myc promoters are responsible for conferring Rb regulation to the fourth promoter of the insulinlike growth factor II gene. We have shown that the transcription factor Sp1 can bind to and stimulate transcription from the retinoblastoma control element motif. Moreover, by using a GAL4-Sp1 fusion protein, we have directly demonstrated that Rb positively regulates Sp1 transcriptional activity in vivo. These results indicate that Rb can function as a positive regulator of transcription and that Sp1 is one potential target, either directly or indirectly, for transcriptional regulation by Rb.
Mol Cell Biol 1992 Jun
PMID:The retinoblastoma gene product regulates Sp1-mediated transcription. 158 49

The L1 cell adhesion molecule was initially identified and characterized in mouse as a cell-surface glycoprotein that mediates neuron-neuron and neuron-Schwann cell adhesion. We have characterized L1 in humans using cDNA structural and mRNA expression analyses. We present the entire coding sequence for human L1, which predicts a 1253-amino acid protein displaying a signal sequence, transmembrane segment, RGD sequence, and potential glycosylation and phosphorylation sites. Nucleotide and deduced amino acid sequence identities between human and mouse L1 are 85% and 87%, respectively. In contrast, the amino acid identity between human L1 and the L1-related molecule chicken Ng-CAM is only 45%. Using Northern blot analyses, a single L1 transcript of 5.5 kb is detected in human fetal brain and in neuroblastoma (IMR-32) and retinoblastoma (Y-79) cell lines. L1 is also expressed in the rhabdomyosarcoma cell lines RD and A-204, which display several muscle characteristics. Two forms of L1, which differ by the presence or absence of a 12-bp cytoplasmic segment, are expressed in both human and mouse. This segment is encoded by a single exon that can be alternately spliced to give rise to the two forms, which appear to be expressed in tissue-specific patterns.
J Mol Neurosci 1992
PMID:Variants of human L1 cell adhesion molecule arise through alternate splicing of RNA. 162 59

The predominant effect of TGF-beta 1 on cell proliferation is inhibition. Earlier studies demonstrated that TGF-beta 1 inhibition of skin keratinocyte proliferation involves suppression of c-myc transcription and indirect evidence suggested that the protein product of the retinoblastoma gene (pRB) may be involved in this process. Skin keratinocytes transformed by SV40 and human papilloma virus-16 (HPV-16) or HPV-18 resisted growth inhibition and suppression of c-myc mRNA by TGF-beta. Transient expression of HPV-16 E7 gene, adenovirus E1A, and SV40 large T antigen (TAg) blocked the TGF-beta 1 suppression of c-myc transcription. Studies with transformation-defective mutants of E1A and TAg suggested that a cellular protein(s) that interacts with a conserved domain of the DNA tumor virus oncoproteins mediates TGF-beta 1 suppression of c-myc transcription and keratinocyte growth. Transient expression of pRB in skin keratinocytes repressed human c-myc promoter/CAT transcription as effectively as TGF-beta 1. The same c-myc promoter region, termed the TGF-beta Control Element (TCE), was required for regulation by both TGF-beta 1 and pRB. TCE bound a cellular protein of approximately 106 kDa and this binding was decreased by TGF-beta 1 treatment. Our data indicate that pRB can inhibit c-myc transcription and suggest the involvement of cellular factor(s) in addition to pRB in the TGF-beta 1 pathway for the suppression of c-myc transcription and growth inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Reprod Dev 1992 Jun
PMID:TGF-beta regulation of epithelial cell proliferation. 163 56

Y-79 human retinoblastoma cells can be induced to express significant quantities of functional D2 dopamine receptors after attachment and differentiation with sodium butyrate. In membranes prepared from differentiated Y-79 cells, the D2 dopaminergic antagonist [3H] methylspiperone exhibits a KD of 77 pm and a Bmax of 60 fmol/mg of protein, whereas the antagonist [125I]iodosulpride reveals a KD of 0.77 nM and a Bmax of 40 fmol/mg of protein. Dopamine also induces a pharmacologically specific, pertussis toxin-sensitive, dose-dependent inhibition of forskolin-stimulated adenylyl cyclase activity, with an EC50 of 2 microM and a maximal response at 100 microM (approximately 50% enzyme inhibition). Pretreatment of the cells with dopamine results in a diminution in the subsequent ability of dopamine to inhibit adenylyl cyclase activity. This effect is time dependent, reaching maximal desensitization after approximately 24 hr. The dopamine dose-response curve for inducing desensitization exhibits an EC50 of approximately 2-3 microM and a maximal response at approximately 0.1-1 mM, similar to that for inhibiting adenylyl cyclase activity. After maximal desensitization, the EC50 for dopamine-induced inhibition of adenylyl cyclase activity is increased greater than 20 fold (lower affinity) and the maximum inhibition is decreased to approximately 15%, representing an approximately 70% desensitization. The agonist-induced desensitization is pharmacologically specific, inasmuch as preincubation of the cells with the dopaminergic agonists epinine and (+-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene or the D2-selective agonist N-0434 also results in desensitization of dopamine-induced inhibition of enzyme activity, whereas preincubation with the D1-selective agonist SKF-38393 or with the nondopaminergic agonists isoproterenol and serotonin results in little or no desensitization. Preincubation of the cells with dopamine also promotes a time-dependent increase (approximately 3-fold) in the KD for [3H]methylspiperone, with no change in its Bmax. In contrast, after dopamine preincubation, the KD for [125I]iodosulpride is unchanged, whereas its Bmax is reduced by approximately 50% upon maximum desensitization. In addition, agonist pretreatment promotes a functional uncoupling of the D2 receptor, as suggested by a loss of high affinity agonist binding observed in radioligand competition binding assays after desensitization. Upon removal of agonist, the cellular D2 receptor binding activity and functional response recover to control levels within a 24-hr period. These results suggest that prolonged exposure of cells to dopaminergic agonists initiates a desensitization process involving a functional uncoupling of the D2 dopamine receptor as well as a loss of its ligand binding activity.
Mol Pharmacol 1991 May
PMID:Agonist-induced desensitization of D2 dopamine receptors in human Y-79 retinoblastoma cells. 167 85


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