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Biomedical subjects

F Martelli

Publications and source records attributed to F Martelli.

At least 37 records · Page 2Linked to original sources
PubMed1996

The retinoblastoma gene product protects E2F-1 from degradation by the ubiquitin-proteasome pathway.

E2F-1 plays a crucial role in the regulation of cell-cycle progression at the G1-S transition. In keeping with the fact that, when overproduced, it is both an oncoprotein and a potent inducer of apoptosis, its transcriptional activity is subject to multiple controls. Among them are binding by the retinoblastoma gene product (pRb), activation by cdk3, and S-phase-dependent down-regulation of DNA-binding capacity by cyclin A-dependent kinase. Here we report that E2F-1 is actively degraded by the ubiquitin-proteasome pathway. Efficient degradation depends on the availability of selected E2F-1 sequences. Unphosphorylated pRb stabilized E2F-1, protecting it from in vivo degradation. pRb-mediated stabilization was not an indirect consequence of G1 arrest, but rather depended on the ability of pRb to interact physically with E2F-1. Thus, in addition to binding E2F-1 and transforming it into a transcriptional repressor, pRb has another function, protection of E2F-1 from efficient degradation during a period when pRb/E2F complex formation is essential to regulating the cell cycle. In addition, there may be a specific mechanism for limiting free E2F-1 levels, failure of which could compromise cell survival and/or homeostasis.

Carrier Proteins↗
PubMed1996

Characterization of two novel YY1 binding sites in the polyomavirus late promoter.

NF-D is a ubiquitous nuclear factor that has been shown to bind specifically to a DNA element in the polyomavirus regulatory region. In this report, we demonstrate that NF-D is either identical or very similar to a transcription factor that has been variously named YY1, delta, NF-E1, UCRBP, or CF1. Moreover, we show the presence in the polyomavirus genome of a second DNA motif, located 40 bp from the first, which binds YY1/NF-D with high affinity. Both sites lie downstream of the major late transcription initiation sites. By site-directed mutagenesis, we demonstrate that both elements contribute positively to the activity of the late promoter, probably by a cooperative mechanism. We also demonstrate that the requirement of the YY1/NF-D function for late promoter activity varies with the cell line.

3T3 Cells↗
PubMed1995

Somatostatin-induced modulation of inflammation in experimental arthritis.

OBJECTIVE: To study the antiinflammatory effect of different doses of intraarticular somatostatin in experimental arthritis in rabbits. METHODS: Chronic arthritis was induced by a single injection of fibrin into the knee joint of rabbits previously sensitized to this antigen. The effects of sequential intraarticular injections of somatostatin into the rabbit knee, at doses of 500, 750, and 1,000 micrograms, were monitored by measuring knee joint circumferences and hematologic parameters. The measurements were compared with those obtained following use of triamcinolone acetonide and placebo. At the end of the experiments, the knee joints were examined histologically. RESULTS: Somatostatin treatment induced a statistically significant and dose-related reduction of knee joint swelling. This effect was shorter than that produced by triamcinolone acetonide; however, the antiinflammatory activity elicited by successive doses of triamcinolone acetonide declined both in extent and duration, while the effects of somatostatin remained unchanged at each successive treatment. Histopathologic observations showed that both somatostatin and triamcinolone acetonide reduced the inflammatory signs in the joint structures, although triamcinolone acetonide appeared to be more effective. CONCLUSION: These findings suggest that somatostatin exerts an antiinflammatory effect in this model of experimental arthritis and may represent a valid and safer alternative to corticosteroids for intraarticular therapy of arthritis.

Animals↗
PubMed1994

Defective human retinoblastoma protein identified by lack of interaction with the E1A oncoprotein.

Inactivating mutations of the retinoblastoma susceptibility gene (Rb) are involved in the pathogenesis of hereditary and sporadic retinoblastoma. Alterations in the Rb gene have also been found in several other human tumors occurring with epidemiological incidence higher than that of retinoblastoma. Four human malignant glioma cell lines were examined for abnormalities in the retinoblastoma gene product (pRb), using a procedure based on the interaction of pRb with an in vitro-translated adenovirus E1A oncoprotein. In the CRS-A2 cell line, derived from a glioblastoma multiforme, pRb did not bind with the in vitro-translated E1A protein. Restriction analysis of the CRS-A2 Rb gene and Rb mRNA expression provided patterns that could not be distinguished from the other glioma cell lines. Further investigation revealed the presence of a truncated pRb in the CRS-A2 cell line, due to a nucleotide insertion in the coding sequence at position 2550. In addition, this truncated Rb protein was undetectable in phosphorylated form. The binding assay with the in vitro-translated E1A was also used to study other cell lines with known mutations in the Rb gene. This method, which evaluates the interaction between in vitro-translated E1A and the pRb, is proposed as a rapid screening for detecting functional alterations in the retinoblastoma protein.

Adenovirus E1A Proteins↗
PubMed1994

MyoD induces retinoblastoma gene expression during myogenic differentiation.

In skeletal muscle cells permanent withdrawal from the cell cycle is a prerequisite for terminal differentiation. The muscle-specific transcription factor MyoD can activate downstream muscle structural genes and myogenic conversion in many different cell types. It has been demonstrated that the product of the retinoblastoma susceptibility gene, with its growth-suppressive activity, is involved in the myogenic function of MyoD (Caruso et al., 1993; Gu et al., 1993). The present study characterises the modulation of retinoblastoma (Rb1) mRNA levels during myogenic differentiation of the murine C2 cell line and provides evidence that the muscle-specific regulatory factor MyoD enhances Rb1 gene transcription. We demonstrate that MyoD mediates the transactivation of a CAT construct whose expression is driven by the human Rb1 gene promoter, and that this is not a consequence of direct binding of MyoD to an E-box DNA sequence motif present in the Rb1 promoter sequences. In addition we have tested the capability of several MyoD mutant proteins of inducing the Rb1 promoter CAT construct. Our results indicate that the MyoD function required for induction of Rb1 promoter activity is distinct from its myogenic function.

Animals↗
PubMed1994

General pharmacology studies on recombinant human follicle stimulating hormone.

Follicle stimulating hormone (FSH) is a heterodimeric glycoprotein secreted by anterior pituitary cells. Its main actions are to lead ovarian follicles to maturation and to maintain spermatogenesis. Up to now the FSH preparations used in clinical practice (CAS 9002-68-0 and CAS 97048-13-0) have been purified from human postmenopausal urine. Only recently, a product was successfully obtained by recombinant-DNA technology, r-hFSH (Gonal-FTM). This recombinant protein is highly pure and has a very high specific activity. In view of its clinical use, this hormone has been submitted to an extensive panel of general pharmacology studies with the aim of defining its pharmacological profile and determine possible side effects not related to the main therapeutic action. Subcutaneous or intravenous doses of 5 to 500 IU/kg were assayed in several tests for their effects in vivo on various systems in different animal species. The substance under study was also tested in vitro on isolated guinea-pig ileum preparations at final concentrations of 0.05 to 2 IU/ml of bath. The results of this study showed that r-hFSH does not influence the general activity and behaviour of mice, as measured by the multidimensional Irwin's test. Similarly, the drug was not found to affect the normal body temperature in rats nor the locomotor activity in mice for as long as 7 h post-injection; in addition, it was not found to induce pharmacologically significant alterations of the cardiovascular and respiratory parameters in rats and dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

[Introductory notes on the origin of phrenology: the work of Vincenzo Malacarne].

The authors examine and evince the links between F.J. Gall's phrenology and Vincenzo Malacarne's studies of encephalous anatomy and mental disorders, especially in the ideas developed by the latter from 1760 to 1794. Malacarne came to believe in those years that mental disorders were organic in nature, being exhibited through alterations in the endocranium organs that could be anatomically detected and diagnosed by studying the patient's cranium. His correspondence with Bonnet enabled Malacarne to anticipate Gall in positing that the faculties of the intellect are congenital and those of the endocranium are organs consisting of individual parts each of which controls a specific intellectual activity. This in turn strengthened Malacarrne's conviction that the cranium's structure matched the development of its parts and led him to invent the cephalometer. Thus convinced of the compound nature of the endocranium's organs, Malacarne went on to develop Bonnet's thesis whereby the peculiarity of the nerve cells and their interaction were assigned a central role in intellectual activities. Yet, despite the evident fact that Malacarne attributed to the cerebellum functions proper to the brain, the points at which his and Gall's ideas overlapped were such as to make ambiguous the former's violent polemics against the latter. Many of the cricticisms he directed at Gall seemed to be dictated by Malacarne's desire to side with Napoleon's and the Catholic Church's condemnation of the former. Others showed that Malacarne wove together personal motives, especially irritation over Gall's outright rejection of his Encefalotomia and scientifically well-grounded criticism of Gall's erroneous ideas concerning the substance of the cortex and the latter's links to nerves, to name the most prominent of many such errors. Even more damaging was Malacarne's unfounded allegation that Gall had less than a thorough grasp of anatomy in that it led the Italian medical establishment to view phrenology as a popular science for many decades thereafter.

Encephalitis↗
PubMed1993

Regulation of MyoD gene transcription and protein function by the transforming domains of the adenovirus E1A oncoprotein.

It has been demonstrated that the adenovirus E1A gene products inhibit myogenic differentiation in the mouse C2 muscle cell line. During myogenic differentiation, cell growth and tissue-specific gene expression are mutually exclusive. Since E1A exerts multiple effects on different cellular pathways through alteration of cell growth control and transcriptional regulation, we investigated in more detail the molecular mechanisms underlying the inhibitory effect of E1A on myogenic differentiation. To this end, we used mutant derivatives of E1A that lack the 'conserved domain' sequences to which the functional domains of E1A have been mapped, and we observed the effect of constitutive expression of these E1A mutants on myogenesis in the murine C2 muscle cell line. Our results demonstrate that E1A interferes with myogenesis through at least two mechanisms: (i) the inhibition of MyoD expression; (ii) the repression of MyoD-dependent transcriptional activation. In addition, we demonstrate also that the repression of MyoD transcription depends upon sequences located in the N-terminus of E1A and correlates well with the site of E1A/p300 association. Further, the inhibition of transcriptional activation by MyoD depends both on conserved region 1 and on conserved region 2, the two transforming domains of E1A. We demonstrate also that a similar inhibitory effect on the MyoD transactivating function is provided by the polyomavirus and SV40 large T oncoproteins.

Adenovirus E1A Proteins↗
PubMed1991

Selenium status and effect of selenium supplementation in a group of elderly women.

Plasma selenium was determined in 92 elderly women: a marked decrease was observed from the age of 65 years. Se-status in 20 elderly women was explored by investigation of the effects of 30 days' Se-supplementation with enriched tablets (Selevit-E) 66 micrograms per day. Serial determination was performed for Se plasma, e-GSH-Px (glutathione peroxidase), MDA (malondialdehyde) and Vitamin E. Significant changes were observed in Se, e-GSH-Px and MDA.

Aged↗
PubMed1990

Short-term effects of diethylaminoethyl-dextran on postprandial gastrointestinal hormone responses in man.

The effects of oral diethylaminoethyl-dextran (3 g total), taken 30 min before a standard mixed test meal, on plasma glucose, total cholesterol, triglycerides, total lipids, gastrin-like immunoreactivity, bombesin-like immunoreactivity, gastric-inhibitory-polypeptide-like immunoreactivity and neurotensin-like immunoreactivity were evaluated in eight healthy volunteers following a double-blind protocol. Incremental peak plasma concentrations of total lipids and triglycerides were significantly reduced by pretreatment with diethylaminoethyl-dextran pretreatment, while peaks of plasma glucose and total cholesterol were not significantly affected. Diethylaminoethyl-dextran also inhibited postprandial gastrin-like gastric-inhibitory-polypeptide-like and neurotensin-like immunoreactivity; by contrast, bombesin-like immunoreactivity was not significantly modified. The present study indicates that diethylaminoethyl-dextran is able to regulate some postprandial metabolic and hormonal parameters in man; consequently it might be useful in the treatment of hyperlipoproteinaemia and obesity.

Adult↗
PubMed1989

GABA-A-mediated gastrin release induced by baclofen in the isolated vascularly perfused rat stomach.

In order to investigate the role of peripheral GABA-B receptors, the effects of the putative GABA-B agonist baclofen on immunoreactive gastrin release from an isolated vascularly perfused rat stomach preparation were examined. The vascular infusion of baclofen at graded concentrations induced a dose-dependent increase in gastrin release; this was unaffected by the GABA-B antagonist delta-aminovaleric acid, but was fully prevented by the selective GABA-A antagonist bicuculline as well as by atropine or tetrodotoxin. These results suggest that the stimulant effects of baclofen are mediated by nervous cholinergic structures associated with GABA-A receptors, and indicate that this GABA-B agonist must be regarded as a partial agonist of peripheral GABA-A receptors.

Amino Acids↗
PubMed1988

An analysis of the effects of galanin on gastric acid secretion and plasma levels of gastrin in the dog.

The effects of galanin on gastric acid secretion and plasma levels of gastrin were studied in conscious dogs chronically fitted with gastric fistulas. Continuous i.v. infusion of galanin (2 micrograms.kg-1.h-1) for 2 h did not affect unstimulated total acid output or plasma levels of gastrin. In contrast, simultaneous i.v. infusion of galanin (1-2 micrograms.kg-1.h-1) inhibited the bombesin-stimulated output of acid whereas the effects of bombesin on gastrin output were not significantly modified. Galanin (2-4 micrograms.kg-1 i.v.) also depressed the secretory response to 2-deoxy-D-glucose without significantly affecting plasma gastrin levels. Galanin (2-4 micrograms.kg-1 i.v.) did not depress bethanechol-stimulated gastric acid output or inhibit histamine-stimulated gastric acid secretion. These findings indicate that glanin inhibits the bombesin- and 2-deoxy-D-glucose-stimulated secretion of gastric acid in conscious dogs by an action which is probably exerted at the level of the cholinergic nerve terminals.

Animals↗