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S J Weintraub

Publications and source records attributed to S J Weintraub.

12 recordsLinked to original sources
PubMed2000

E2F is required to prevent inappropriate S-phase entry of mammalian cells.

E2F is a family of transcription factors that regulates the cell cycle. It is widely accepted that E2F-mediated transactivation of a set of genes is the critical activity that governs cellular progression through G(1) into S phase. In contrast to this hypothesis, we demonstrate that E2F actually suppresses the onset of S phase in two cell types when the cells are arrested by gamma irradiation. Our findings indicate that in these cells, the critical event triggering progression from G(0)/G(1) arrest into S phase is the release of E2F-mediated transrepression of cell cycle genes, not transactivation by E2F. Furthermore, our data suggest that E2F-mediated transactivation is not necessary for the G(1)/S-phase transition in these cells.

Animals↗
PubMed1998

Stepwise recruitment of components of the preinitiation complex by upstream activators in vivo.

Recently, it was found that if either the TATA binding protein or RNA polymerase II holoenzyme is artificially tethered to a promoter, transcription is activated. This finding provided presumptive evidence that upstream activating proteins function by recruiting components of the preinitiation complex (PIC) to the promoter. To date, however, there have been no studies demonstrating that upstream factors actually recruit components of the PIC to the promoter in vivo. Therefore, we have studied the mechanism of action of two disparate transactivating domains. We present a series of in vivo functional assays that demonstrate that each of these proteins targets different components of the PIC for recruitment. We show that, by targeting different components of the PIC for recruitment, these activating domains can cooperate with each other to activate transcription synergistically and that, even within one protein, two different activating subdomains can activate transcription synergistically by cooperating to recruit different components of the PIC. Finally, considering our work together with previous studies, we propose that certain transcription factors both recruit components of the PIC and facilitate steps in transcriptional activation that occur subsequent to recruitment.

Cells, Cultured↗
PubMed1996

Inactivation of tumor suppressor proteins in lung cancer.

It had been thought that the central molecular event in the malignant transformation of a cell is the mutation of certain oncogenes-and the resultant dysregulated activation of their encoded proteins. During the past decade, however, it has become clear that alteration of the activity of the protein products of tumor suppressor genes, through mutation or at the posttranslational level, is an equally basic and universal process in tumorigenesis. These proteins normally modulate cellular proliferation in the developing and adult organism, functioning as tumor suppressors by inhibiting inappropriate cell division. Therefore, inactivation of the normal function of tumor suppressor proteins removes important regulatory constraints on the cell, permitting the accelerated growth of cancerous tissue. The genesis of lung cancer is though to involve between 10 and 20 mutations. Of these, several are now known to involve tumor suppressor genes. In this review I will discuss the mechanism of tumor suppression by the protein encoded by one of these, the retinoblastoma gene, to illustrate precisely why the inactivation of tumor suppressors is a requisite step in cellular progression to lung and other carcinomas.

Genes, Tumor Suppressor↗
PubMed1995

Mechanism of active transcriptional repression by the retinoblastoma protein.

The retinoblastoma tumour-suppressor protein (Rb) belongs to a family that share a motif known as the pocket. The pocket was originally identified as the region of Rb required for binding to oncoproteins from DNA tumour viruses, which disrupt the binding of Rb to the E2F family of cell-cycle transcription factors (referred to collectively here as E2F). Rb switches E2F sites from positive to negative elements, suggesting that Rb-E2F is an active complex that blocks transcription. Here we report that Rb is selectively recruited to promoters through E2F, where it in turn inactivates surrounding transcription factors by blocking their interaction with the basal transcription complex. We suggest that this repressor activity is essential for inhibiting promoters that contain enhancers in addition to E2F sites.

Carrier Proteins↗
PubMed1992

Retinoblastoma protein switches the E2F site from positive to negative element.

Originally E2F sites were identified as elements in the promoters of adenovirus early genes that are necessary for activation of these genes by the early protein E1a (ref. 1). E2F promoter elements have been shown to be important for transcriptional activation of several genes critical for progression through the cell cycle. During the G1 phase of the cell cycle, the E2F protein forms a complex with the cell-cycle protein Rb (ref. 5) and it has been suggested that this binding of Rb to E2F inactivates E2F (ref. 5). Here we show that Rb-E2F is an active complex that, when bound to the E2F site, inhibits the activity of other promoter elements and thus silences transcription. We propose that the ability of this complex to inhibit transcription is integral to the function of Rb and provide evidence that E2F is a positive element in the absence of an active form of Rb. It has been shown that binding of Rb to E2F depends on the phosphorylation state of Rb (only the underphosphorylated form binds) and that the phosphorylation state of Rb changes during progression through the cell cycle. We therefore suggest that the E2F site alternates between a positive and negative element with the phosphorylation/dephosphorylation cycle of Rb. This cyclic activity may be responsible for activating and then inhibiting genes during the cell cycle.

Adenoviridae↗
PubMed1992

Interaction of a common factor with ATF, Sp1, or TATAA promoter elements is required for these sequences to mediate transactivation by the adenoviral oncogene E1a.

The adenovirus protein E1a stimulates transcription of both viral and cellular genes. Unlike most other transcription factors, it induces transactivation through several different promoter elements. The mechanism by which elements of diverse sequence mediate the effect of E1a is the focus of this study. Three E1a-responsive elements (an ATF site, an Sp1 site, and a TATA box containing the sequence TATAA) were studied to determine whether their interaction with a common factor is necessary for transactivation. In transfection assays, each element was used as a competitor against promoter constructs containing the other elements. The elements as competitors had no effect on basal transcription, but each competitor completely inhibited transactivation by E1a. Competitors that were not E1a responsive failed to inhibit transactivation. Therefore, either E1a itself or an E1a-inducible factor interacts with each of the elements to cause transactivation, most likely though an association with each element's specific binding protein.

Activating Transcription Factors↗
PubMed1991

Glycoprotein synthesis and secretion. Expression of fibronectin and its cell surface receptors.

Fibronectin (FN) is an extracellular matrix protein that acts as a substrate for cell migration and adhesion during development. Cells adhere to FN through integral membrane proteins that are members of the integrin family of adhesion molecules. The interaction between cells and FN is important in a number of biologic processes, including gastrulation, hematopoietic differentiation, neural crest cell migration, cardiac development, branching morphogenesis in lung, wound healing, tumorigenesis, and metastasis. Expression of FN and its receptors is controlled by a number of hormones and growth factors as well as by tissue-specific factors. Here, the molecular aspects of how expression of these genes is controlled are reviewed, with particular emphasis on promoter regulator elements that modulate expression.

Fibronectins↗
PubMed1989

The inhaled bronchodilators ipratropium bromide and metaproterenol in adults with CF.

Ten patients with CF who were more than 18 years old, participated in a double-blind, placebo-controlled study evaluating the efficacy of inhaled ipratropium bromide and metaproterenol as bronchodilators. The mean FEV1 of the group improved 17.1 percent after treatment with ipratropium bromide, 12.5 percent after metaproterenol treatment, and 16.6 percent after treatment with both of these medications together. There was no significant difference between these responses and patients who responded to one treatment tended to respond to the others. The side effects with these medications were minimal. When compared with patients in previous studies, our patients, who were much older as a group, demonstrated a greater degree of bronchodilation with ipratropium bromide and metaproterenol, as well as a greater degree of bronchoconstriction with placebo.

Administration, Inhalation↗
PubMed1986

Markedly delayed postoperative malignant hyperthermia.

Malignant hyperthermia (MH) may be triggered by exposure to commonly employed anesthetic agents and muscle relaxants, and often manifests itself during the period of anesthesia. Delayed-onset MH occurring one to four hours postoperatively has been described in isolated case reports. A case of delayed-onset MH occurred 11 hours following routine tonsillectomy and adenoidectomy. The patient demonstrated tachypnea, tachycardia, hyperthermia, and metabolic acidosis. Prompt intravenous administration of dantrolene sodium was therapeutic. Serial serum creatine phosphokinase evaluation verified the diagnosis of MH. The implications of delayed-onset MH and the importance of preoperative screening for potentially susceptible individuals are discussed.

Adenoidectomy↗