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

Ectopic expression of cyclins D1 and E was previously shown to accelerate the G1/S-phase transition, indicating that both classes of G1 cyclin control an event(s) that is rate limiting for entry into S phase. In order to determine whether cyclins D1 and E control the same or two different rate-limiting events, we have created cell lines that express both cyclins in an inducible manner. We show here that ectopic expression of both cyclins E and D1 in the same cell has an additive effect on shortening of the G1 interval relative to expression of any single cyclin. In order to further explore the molecular basis for G1 cyclin action, we used cell lines capable of expressing cyclin D1, E, or both prematurely and measured the effect of cyclin expression in early G1 on phosphorylation of the retinoblastoma susceptibility gene product (pRb). We show here that while premature expression of either cyclin alone advances the G1/S-phase transition to the same extent, premature expression of cyclin D1 leads to immediate appearance of hyperphosphorylated pRb, while premature expression of cyclin E does not. Ectopic expression of both cyclins E and D1 in the same cell has an additive effect on shortening of the G1 interval, while the effect on pRb phosphorylation is similar to the effect of cyclin D1 alone. These results suggest that cyclins E and D1 control two different events, both rate limiting for the G1/S-phase transition, and that pRb phosphorylation might be the rate-limiting event controlled by cyclin D1.
Mol Cell Biol 1995 Jul
PMID:Different roles for cyclins D1 and E in regulation of the G1-to-S transition. 779 52

Although many lines of evidence indicate that the cellular protein p107 is closely related to the retinoblastoma protein, the exact function of the p107 gene and its regulation are presently not known. To investigate the molecular mechanism controlling expression of the human p107 gene, a 5' flanking sequence of this gene was isolated and shown to promote high-level expression of a luciferase reporter gene in cycling human 293 and Saos-2 cells. Sequencing and transcription mapping analyses showed that the human p107 promoter is TATA-less and contains a tandem, direct repeat of E2F-binding sites, with the 3' copy overlapping the major transcription initiation site. Deletion analysis of the p107 promoter showed that a promoter DNA fragment containing only the two E2F sites together with the leader sequence could direct relatively efficient expression in 293 cells. Site-directed mutagenesis of these E2F sites revealed that although both sites were important for p107 promoter activity, mutation on the proximal, initiation site copy of the E2F site showed a stronger effect. The human p107 promoter could be repressed by the retinoblastoma protein and its own gene product. Interestingly, the repression was found to be mediated through the 5' copy of the E2F site. These studies demonstrate for the first time differential roles of two tandem E2F sites in promoter regulation.
Mol Cell Biol 1995 Jul
PMID:Differential roles of two tandem E2F sites in repression of the human p107 promoter by retinoblastoma and p107 proteins. 779 62

Germline mutations in the RB1 gene confer hereditary predisposition to retinoblastoma. We have performed a mutation survey of the RB1 gene in 232 patients with hereditary or non hereditary retinoblastoma. We systematically explored all 27 exons and flanking sequences as well as the promotor. All types of point mutations are represented and are found unequally distributed along the RB1 gene sequence. In the population we studied, exons 3, 8, 18 and 19 are preferentially altered. The range of frequency of detection of germline mutations is about 20%, indicating that other mechanisms of inactivation of RB1 should be involved. The spectrum of mutations presented here should help to improve the clinical management of retinoblastoma and to understand the molecular mechanisms leading to tumorigenesis.
Hum Mol Genet 1995 Mar
PMID:Spectrum of germline mutations in the RB1 gene: a study of 232 patients with hereditary and non hereditary retinoblastoma. 779 91

The interaction of the retinoblastoma susceptibility gene product (Rb)-related p107 protein with the E2F transcription factor in S-phase cells facilitates the formation of a multicomponent complex also containing cyclin A and the p33cdk2 kinase. We have created a series of p107 mutants to assess the ability of p107 to inhibit E2F function and the role of the cyclin A/cdk2 complex in this process. We find that p107 mutants that do not bind to E2F also fail to repress E2F-dependent transcription. Moreover, we find that the ability of p107 to suppress E2F-dependent transcription is not dependent on the ability of p107 to associate with cyclin A/cdk2. Finally, an analysis of the ability of the p107 mutant proteins to suppress cell growth suggests that both E2F-dependent and E2F-independent events correlate with this activity.
Mol Cell Biol 1995 Jan
PMID:The Rb-related p107 protein can suppress E2F function independently of binding to cyclin A/cdk2. 779 40

The Wilms tumour (WT1) gene was first localized through its deletion in individuals with the WAGR syndrome (Wilms tumour, aniridia, genitourinary abnormalities and mental retardation). Such individuals have a 30-50% lifetime risk of developing Wilms tumour and carry constitutional interstitial deletions of chromosome 11p13, including the WT1 gene. Second primary tumours occurring in such individuals might also be related to their genetic predisposition to cancer, as shown for hereditary retinoblastoma. We have found a mutation in the zinc finger region of the remaining WT1 allele in a case of acute myeloid leukaemia developing in a Wilms tumour survivor with the WAGR syndrome. This mutation would be predicted to disrupt DNA binding by this developmentally regulated transcription factor. This finding implicates the WT1 gene in the regulation of myelopoiesis and suggests that WT1 mutations may be found in some sporadic leukaemias.
Hum Mol Genet 1994 Sep
PMID:The Wilms tumour (WT1) gene is mutated in a secondary leukaemia in a WAGR patient. 783 22

It is widely believed that in mammalian cells the cellular transcription factor (DRTF1/E2F integrates cell-cycle events with the transcription apparatus by interacting with important regulators of the cell cycle, such as the retinoblastoma gene product (pRb) and related proteins, cyclins, and cyclin-dependent kinases. Here, we have defined DRTF1/E2F in Xenopus laevis that, like its mammalian counterpart, specifically binds to the E2F site, is regulated during development, and interacts with pRb and related proteins. We have isolated cDNAs that encode the functional homologue of mammalian DP-1, X1 DP-1, together with a close relative, X1 DP-2. X1 DP-1, which is highly conserved with murine DP-1, is a major DNA binding component of X1 DRTF1/E2F. Both DP-1 and DP-2 synergistically interact with members of the E2F family of proteins, E2F-1, E2F-2, and E2F-3, to generate DNA binding complexes that specifically recognize the E2F site and functionally interact with E2F-1 in E2F site-dependent transcriptional activation of cellular genes. DP-1 and DP-2 encode maternally stored transcripts that are expressed during early development. In the adult however, the expression of DP-1 and DP-2 is tissue restricted. This study therefore defines a new family of transcription factors, the DP proteins, members of which can interact combinatorially with E2F proteins to generate an array of DNA binding complexes that integrate cell-cycle progression with the transcription apparatus through the E2F binding site. The tissue-specific expression of DP family members suggests that the combination of DP/E2F heterodimers that constitute DRTF1/E2F is influenced by the phenotype of the cell.
Mol Biol Cell 1994 Oct
PMID:Molecular characterization of Xenopus laevis DP proteins. 786 76

A screening method based on multiplexed automated fragment length analysis of polymerase chain reaction products was used to identify germline mutations in the RB1 gene. By screening 106 unrelated patients with hereditary retinoblastoma, 20 small deletions (1-18 bp) and seven insertions (1-5 bp) were identified. When collating our data with reported mutations, recurrence of small length mutations was observed at nine sites within the RB1 gene. Most of these contained monotonic runs or direct repeats embedded in homocopolymer tracts. While the majority of mutations resulted in premature truncation, two mutations caused an in-frame loss of F755 and G540 to E545, respectively. A genotype-phenotype comparison of patients carrying different small length mutations did not reveal any consistent relation. Particularly, the two patients with in-frame mutations showed a high number of tumours consistent with regular-penetrance retinoblastoma.
Hum Mol Genet 1994 Dec
PMID:Spectrum of small length germline mutations in the RB1 gene. 788 18

We have examined regulation of the E2F transcription factor during differentiation of muscle cells. E2F regulates many genes involved in growth control and is also the target of regulation by diverse cellular signals, including the RB family of growth suppressors (e.g., the retinoblastoma protein [RB], p107, and p130). The following aspects of E2F function and regulation during muscle differentiation were investigated: (i) protein-protein interactions, (ii) protein levels, (iii) phosphorylation of the E2F protein, and (iv) transcriptional activity. A distinct E2F complex was present in differentiated cells but not in undifferentiated cells. The p130 protein was a prominent component of the E2F complex associated with differentiation. In contrast, in undifferentiated cells, the p107 protein was the prominent component in one of three E2F complexes. In addition, use of a differentiation-defective muscle line provided genetic and biochemical evidence that quiescence and differentiation are separable events. Exclusive formation of the E2F-p130 complex did not occur in this differentiation-defective line; however, E2F complexes diagnostic of quiescence were readily apparent. Thus, sole formation of the E2F-p130 complex is a necessary event in terminal differentiation. Other changes in E2F function and regulation upon differentiation include decreased phosphorylation and increased repression by E2F. These observations suggest that the regulation of E2F function during terminal differentiation may proceed through differential interaction within the RB family and/or phosphorylation.
Mol Cell Biol 1995 Apr
PMID:Multiple change in E2F function and regulation occur upon muscle differentiation. 789 19

Previously constructed Swiss mouse 3T3 fibroblasts producing polyomavirus large T antigen after addition of dexamethasone were used to study the transcriptional activation by the viral protein of five genes coding for enzymes involved in DNA synthesis and precursor production, namely, dihydrofolate reductase, thymidine kinase, thymidylate synthase, DNA polymerase alpha, and proliferating-cell nuclear antigen. It was found that all these genes, whose expression is stimulated at the G1/S boundary of the cell cycle after growth stimulation by serum addition, are coordinately trans activated when T antigen is induced in cells previously growth arrested by serum withdrawal. Cell lines carrying the information for a mutant form of large T antigen, in which a glutamic acid residue in the binding site for the retinoblastoma protein was changed into aspartic acid, were constructed to test the involvement of an interaction of T antigen with the retinoblastoma protein in this reaction. It was found that the mutated T protein is incapable of stimulating transcription of any one of the genes. The promoter of three of the genes (dihydrofolate reductase, thymidine kinase, and DNA polymerase alpha) unequivocally carries binding sites for transcription factor E2F, suggesting that complexes forming with this growth- and cell cycle-regulating transcription factor are the targets for T antigen. Although there is so far no evidence that thymidylate synthase and proliferating cell nuclear antigen are regulated via E2F, our data indicate that the retinoblastoma protein still is involved in the control of these genes. mRNA for E2F itself increases in amount at the G1/S border in serum-stimulated cells but not during polyomavirus T antigen-induced transcriptional activation of DNA synthesis enzymes in arrested cells.
Mol Cell Biol 1994 Mar
PMID:Coordinated trans activation of DNA synthesis- and precursor-producing enzymes by polyomavirus large T antigen through interaction with the retinoblastoma protein. 790 59

The cell cycle-regulatory transcription factor E2F-1 is regulated by interactions with proteins such as the retinoblastoma gene product and by cell cycle-dependent alterations in E2F-1 mRNA abundance. To better understand this latter phenomenon, we have isolated the human E2F-1 promoter. The human E2F-1 promoter, fused to a luciferase cDNA, gave rise to cell cycle-dependent luciferase activity upon transfection into mammalian cells in a manner which paralleled previously reported changes in E2F-1 mRNA abundance. The E2F-1 promoter contains four potential E2F-binding sites organized as two imperfect palindromes. Gel shift and transactivation studies suggested that these sites can bind to E2F in vitro and in vivo. Mutation of the two E2F palindromes abolished the cell cycle dependence of the E2F-1 promoter. Thus, E2F-1 appears to be regulated at the level of transcription, and this regulation is due, at least in part, to binding of one or more E2F family members to the E2F-1 promoter.
Mol Cell Biol 1994 Oct
PMID:Transcription of the E2F-1 gene is rendered cell cycle dependent by E2F DNA-binding sites within its promoter. 762 59


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