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Biomedical subjects

M Laiho

Publications and source records attributed to M Laiho.

At least 37 records · Page 2Linked to original sources
PubMed1993

Three methods of oral health education in secondary schools.

In 1990, three methods of oral health education (OHE) were implemented in three secondary schools in the city of Pori, Finland, one method in each school. The traditional OHE consisted of a lecture given by a dentist with the aid of transparencies and slides. The peer OHE consisted of a lecture given by six pupils from the upper grades. These pupils used transparencies and extracts of video films and had a classroom exhibition with pictures, slogans, and dental aids and instruments. The self-teaching OHE was based on an exhibition from which the pupils searched for the information themselves. After the programs, the pupils' opinions about the method itself, its contents and implementation, knowledge about certain oral health issues, and the possible effect of the method were determined by a questionnaire. The attitudes and opinions were most positive in the peer OHE group. The traditional OHE was quite well accepted, but the self-teaching method was not very successful. The participants in the traditional OHE more often felt that they had been encouraged to pursue good oral health habits. In all groups, the topic considered to be the most boring was tooth brushing. Peer OHE can be recommended for Finnish secondary schools. The issue of tooth brushing should be played down, however, as too frequent repetition of the topic may cause more negative attitudes towards oral health education and practices.

Adolescent↗
PubMed1993

Human retinoblastoma gene product prevents c-Ha-ras oncogene mediated cellular transformation of mouse fibroblasts.

Suppression of tumor formation and restoration of normal growth of cells has been an insignia that the retinoblastoma gene (RB1) functions as a tumor suppressor gene. The tumor suppressive functions of RB are suggested to associate with regulation of cell cycle events or gene transcription. We have analysed here the interactions of RB and c-Ha-ras oncogene by gene transfection studies. Mouse fibroblasts stably expressing high levels human wild type (wt) pRB or mutant pRB were transfected with genomic or LTR promoter driven c-Ha-ras(Val-12) expression vectors. We find that expression of normal, but not mutant RB protein in the cells prevents c-Ha-ras oncogene mediated cellular transformation and colony formation in soft agar. Analysis of stable RB and genomic c-Ha-ras cell transfectants for expression of pRB and p21ras by immunoblotting indicates a strong correlation with the presence of high levels of RB protein and inhibition of ras-transformation. Moreover, during culturing the RB and genomic c-Ha-ras expressing clones a progressive transformation of phenotypically normal clones was observed which paralleled loss or decrease of RB expression and concomitant increase in p21ras production. These findings suggest a functional cross-talk between RB protein and p21ras, which balances the cell phenotype between normal and transformed states.

3T3 Cells↗
PubMed1992

TGF beta signals through a heteromeric protein kinase receptor complex.

Transforming growth factor beta (TGF beta) binds with high affinity to the type II receptor, a transmembrane protein with a cytoplasmic serine/threonine kinase domain. We show that the type II receptor requires both its kinase activity and association with another TGF beta-binding protein, the type I receptor, to signal growth inhibition and early gene responses. Receptors I and II associate as interdependent components of a heteromeric complex: receptor I requires receptor II to bind TGF beta, and receptor II requires receptor I to signal. This mode of operation points to fundamental differences between this receptor and the protein-tyrosine kinase cytokine receptors.

Amino Acid Sequence↗
PubMed1992

Transforming growth factors-beta as regulators of cellular growth and phenotype.

An increasing number of cDNAs and polypeptides have been ascribed to the transforming growth factor-beta (TGF-beta) superfamily. It has become evident that this evolutionally well-conserved gene family has representatives in many organisms, from invertebrates to mammalians. As new members are being identified, the knowledge of their biological significance is derived not only from studies of their effects in various in vitro models, but also of their organismal expression during different stages of embryogenesis and morphogenesis. The major described functions of the TGF-beta and like proteins seem to be the regulation of cell proliferation, phenotype, and differentiation. Part of these effects may be attributed to changes in the adhesive properties of the cells and integrity of their extracellular matrices modulated by TGF-beta. Identification of the new members of the TGF-beta family, their biological effects, cell-surface receptors, and cell or tissue-specific expression will be invaluable in trying to understand the purpose of many seemingly alike multiregulators.

Animals↗
PubMed1992

Transforming growth factor-beta.

This chapter has described some of the most salient features of the biology of the TGF-beta s. The TGF-beta s are of great interest as growth inhibitors, regulators of cell phenotype and regulators of cell adhesion. The various TGF-beta isoforms are highly conserved and display a complex pattern of interactions with multiple membrane receptor components. Activation of these receptors leads to inhibition of epithelial cell proliferation by a mechanism that may involve proteins related to the growth suppressor, RB. TGF-beta receptors are also coupled to mechanisms that control expression of differentiation commitment genes and differentiated cell functions. TGF-beta can affect cell proliferation and differentiation through indirect mechanisms involving regulation of expression of cytokines, extracellular matrix molecules and their respective receptors. These responses strongly influence the growth and phenotype of an array of cell types. Excess or reduced TGF-beta activity may contribute to the pathogenesis of certain fibrotic disorders and certain hyperproliferative disorders including cancer, respectively.

Cell Differentiation↗
PubMed1991

Responsiveness to transforming growth factor-beta (TGF-beta) restored by genetic complementation between cells defective in TGF-beta receptors I and II.

Selection of mutant Mv1Lu mink lung epithelial cells resistant to growth inhibition by transforming growth factor-beta (TGF-beta) has led to the isolation of cell clones with distinct alterations in type I and II TGF-beta receptors. Certain mutant clones present a decreased number or complete loss of detectable type I receptor. Other clones show a loss and/or altered electrophoretic mobility of the type II receptor, with concomitant loss of the type I receptor. Using somatic cell hybridization analysis we demonstrate the recessive nature of these mutants with respect to the wild-type phenotype and define various mutant complementation groups. Among these, hybrids between cells that express only type II receptor (R mutants) and cells that express neither receptor type (DRa mutants) rescue wild-type expression of type I receptors. Moreover, these hybrids regain full responsiveness to TGF-beta 1, as measured by inhibition of DNA synthesis as well as stimulation of fibronectin and plasminogen activator inhibitor-1 production. These results provide evidence for an interaction between TGF-beta receptor components I and II and show that, in Mv1Lu cells, expression of both receptor types is required for mediation of biological responses to TGF-beta 1.

Animals↗
PubMed1991

Mechanisms in TGF-beta action.

The various isoforms of TGF-beta are multifunctional. We are exploring pathways of cellular regulation by TGF-beta that lead to suppression of cell proliferation, modulation of cell adhesion and control of cell differentiation. These cellular responses appear to be activated by binding of TGF-beta to a similar set of receptor glycoproteins in all cell types. TGF-beta receptor types I and II are specifically lost in cell mutants that are resistant to TGF-beta. The concomitant loss of these two receptors in certain mutants suggests that they are components of the TGF-beta signal-transducing receptor complex. Inhibition of epithelial cell proliferation by TGF-beta is linked to retention of the retinoblastoma growth suppressor gene product in an underphosphorylated state that is presumed to have growth suppressive activity. Inhibition of myogenic differentiation by TGF-beta involves a block in the expression of the master myogenic differentiation genes, such as myogenin, but appears also to involve up-regulation of extracellular matrix production. Expression of components of the cell adhesion apparatus--cell adhesion receptors and extracellular matrix proteins--is controlled by TGF-beta in an array of cell types. This response could have a great impact on the ability of cells to migrate, home to specific tissue locations and differentiate during development, invasion and metastasis.

Animals↗
PubMed1991

Growth factors in the regulation of plasminogen-plasmin system in tumor cells.

Growth regulatory polypeptides, which act in an autocrine or paracrine fashion, are increasingly implicated in the control of pericellular proteolysis. Representatives of major growth factor families, like EGF, PDGF, IGF, FGF, IL, and TGF beta, and in addition, TNFs have effects both on cell proliferation and proteolytic events. Some of them participate in the control of proteolytic events by affecting pericellular PA activity. These factors regulate the synthesis, secretion, and activity of both PAs and their inhibitors in a cell and factor-specific manner. Interestingly, most of these affect simultaneously the secretion of both PAs and their inhibitors, sometimes concomitantly. In addition to PAs, growth factors modulate secretion of collagenases, transin, and stromelysin, and their respective inhibitors, TIMP. The balance of pericellular proteolytic activity is regulated according to the nature and interaction of various growth factors. Pericellular proteolysis can be modulated by growth factors at different levels. Several growth factors are able to regulate the amount and composition of the extracellular matrices. This, in turn, may affect the interactions of certain growth factors with the pericellular matrix structures. Altered structure of the matrix due to excessive proteolytic activity may thus limit the amount and activity of matrix-associated growth factors. Several growth factors exist in latent forms, and activation of these growth factors often requires proteolytic processing. A regulatory loop is thus formed where active growth factors affect the secretion of proteolytic enzymes and thus the concentrations of active ligands.(ABSTRACT TRUNCATED AT 250 WORDS)

Endopeptidases↗
PubMed1991

Early gene responses to transforming growth factor-beta in cells lacking growth-suppressive RB function.

The growth-suppressive function of the retinoblastoma susceptibility gene product, RB, has been implicated in the mediation of growth inhibition and negative regulation of certain proliferation related genes by transforming growth factor-beta 1 (TGF-beta 1). Early gene responses to TGF-beta 1 were examined in order to determine their dependence on the cell cycle and on the growth-suppressive function of RB. TGF-beta 1, which rapidly elevates the steady-state level of junB and PAI-1 mRNAs and decreases that of c-myc mRNA, induces these responses in S-phase populations of Mv1Lu lung epithelial cells containing RB in a phosphorylated state. Since in this state RB is presumed to lack growth-suppressive activity, the response to TGF-beta 1 was also examined in DU145 human prostate carcinoma cells whose mutant RB product lacks growth-suppressive function. In these cells, TGF-beta 1 also decreases c-myc expression at the transcription initiation level. These results suggests that the c-myc, junB, and PAI-1 responses to TGF-beta 1 are not restricted to the G1 phase of the cell cycle and that down-regulation of c-myc expression by TGF-beta 1 can occur through a mechanism independent from the growth-suppressive function of RB.

Animals↗
PubMed1991

Control of junB and extracellular matrix protein expression by transforming growth factor-beta 1 is independent of simian virus 40 T antigen-sensitive growth-sensitive growth-inhibitory events.

Treatment of Mv1Lu mink lung epithelial cells with transforming growth factor-beta 1 (TGF-beta 1) prevents phosphorylation of the retinoblastoma susceptibility gene product, RB, in late G1 phase of the cell cycle, which is thought to retain RB in a growth-suppressive state. This effect is paralleled by cell cycle arrest in late G1 (M. Laiho, J. A. DeCapric, J. W. Ludlow, D. M. Livingston, and J. Massagué, Cell 62:175-185, 1990). Arrest can be prevented by expression of simian virus 40 T antigen, which binds to underphosphorylated RB, presumably blocking its growth-suppressive activity. The response of cells to TGF-beta 1, however, is complex and includes changes in the levels of expression of genes encoding nuclear transcription factors and extracellular matrix components. To define the relationships among various components of the TGF-beta 1 response, we have investigated the effect of TGF-beta 1 on cells whose growth-inhibitory response to this factor is prevented by T antigen. TGF-beta 1 addition to exponentially growing Mv1Lu cells increased the levels of junB mRNA and of three extracellular matrix proteins: plasminogen activator inhibitor-1, fibronectin, and thrombospondin. Kinetically, the effects on junB and plasminogen activator inhibitor-1 expression occurred faster (half-maximal at 1 to 2 h) than the effects on fibronectin and thrombospondin expression (half-maximal at 6 to 10 h). These effects either preceded or overlapped, respectively, the withdrawal of Mv1Lu cells from the cell cycle. Expression of a transfected T-antigen gene in Mv1Lu cells, however, did not prevent any of these responses to TGF-beta 1. The results indcate that TGF-B1-stimulated expression of junB and extracellular matrix proteins in Mv1Lu cells can occur independently of the T-antigen-sensitive events that lead to growth arrest.

Animals↗
PubMed1990

Distinct transforming growth factor-beta (TGF-beta) receptor subsets as determinants of cellular responsiveness to three TGF-beta isoforms.

Characterization of the three mammalian transforming growth factor-beta (TGF-beta) isoforms, TGF-beta 1, -beta 2, and -beta 3, indicates that TGF-beta 3 is somewhat more potent (ED50 = 0.5 pM versus 2 pM) than TGF-beta 1 and TGF-beta 2 as a growth inhibitor of the Mv1Lu mink lung epithelial cell line. In the fetal bovine heart endothelial (FBHE) cell line, however, TGF-beta 1 and -beta 3 are at least 50-fold more potent than TGF-beta 2 which is a very weak growth inhibitor (ED50 greater than or equal to 0.5 nM). Thus, as growth inhibitors, TGF-beta 1 and -beta 3 resemble each other more than TGF-beta 2. The presence of serum alpha 2-macroglobulin in the FBHE cell assays decreases the biological potency of TGF-beta s, in particular TGF-beta 2. This effect of alpha 2-macroglobulin, however, is not sufficient to explain the low responsiveness of FBHE cells to TGF-beta 2. Evaluation of the role of TGF-beta receptors as determinants of cell-specific responsiveness to TGF-beta isoforms indicates that TGF-beta 1, -beta 2, and -beta 3 have similar affinity for the membrane proteoglycan, betaglycan. They differ, however, in their ability to bind to receptor types I and II which are implicated in TGF-beta signal transduction. TGF-beta 1 is similar, albeit not identical, to TGF-beta 3 and much more potent than TGF-beta 2 as a competitor for binding to the overall population of receptors I and II in all cell lines tested. A subset of receptors I and II has been identified in Mv1Lu cells which has high affinity for TGF-beta 2 (KD approximately 10 pM) and binds this factor at concentrations that are biologically active in Mv1Lu cells. This receptor subset could not be detected in FBHE cells, suggesting that cell-specific differences in the level of high affinity of TGF-beta 2 receptors may lead to cell-specific differences in responsiveness to this isoform. Thus, despite their structural and biological similarities, TGF-beta 1, -beta 2, and -beta 3 diverge in their ability to bind to receptors in a manner that correlates with their potency as growth inhibitors.

Animals↗
PubMed1990

Concomitant loss of transforming growth factor (TGF)-beta receptor types I and II in TGF-beta-resistant cell mutants implicates both receptor types in signal transduction.

A panel of 71 chemically mutagenized Mv1Lu mink lung epithelial cell clones were selected based on their resistance to the growth inhibitory action of transforming growth factor beta 1 (TGF-beta 1) and TGF-beta 2. Characterization of TGF-beta receptors in these mutants indicates that the TGF-beta-binding membrane proteoglycan, betaglycan, is apparently normal in all of them. However, 14 of the mutant clones are defective in TGF-beta receptor type I, and 22 clones are simultaneously defective in receptor types I and II. The clones with type I receptor defects fall into two distinct phenotypes, called R and LR. The R phenotype is characterized by the lack of detectable type I receptors, and has been previously described (Boyd, F. T., and Massagué, J. (1989) J. Biol. Chem. 264, 2272-2278). LR mutants are characterized by expression of low levels of type I receptor and are, like the R mutants, completely resistant to growth inhibition by TGF-beta 1 or -beta 2. Mutant clones that are simultaneously defective in receptor types I and II fall into three distinct phenotypes. These included DRa mutants which are characterized by lack of detectable receptor types I and II, DRb mutants which are characterized by low expression of both receptor types and an anomalously fast electrophoretic mobility of the type II receptor protein. All mutants that have a low level of type II receptor are also defective in type I receptor. In addition to the loss of growth inhibitory response, the receptor-defective mutants described here have lost all other responses to TGF-beta 1 and -beta 2 known to occur in parental Mv1Lu cells. The defects present in these mutant clones are not encountered in clones isolated from nonmutagenized parental Mv1Lu cells or in mutagenized cells that had not been exposed to selection with TGF-beta. The results implicate TGF-beta receptor types I and II in the mediation of a common set of cellular responses to TGF-beta. Furthermore, the high relative frequency of isolation of DR mutants raises the possibility that receptor types I and II interact as part of a common signaling TGF-beta receptor complex.

Affinity Labels↗
PubMed1990

Growth inhibition by TGF-beta linked to suppression of retinoblastoma protein phosphorylation.

The growth-suppressive function of the retinoblastoma gene product, RB, has been ascribed to the underphosphorylated RB form that prevails during G1 phase in the cell cycle. We show that addition of the paracrine growth inhibitor transforming growth factor beta 1 (TGF-beta 1) to Mv1Lu lung epithelial cells in mid to late G1 prevents phosphorylation of RB scheduled for this cell cycle stage and arrests cells in late G1. Expression of SV40 T antigen, a transforming protein that binds underphosphorylated RB, does not block the effect of TGF-beta 1 on RB phosphorylation but greatly reduces the growth-inhibitory response to TGF-beta 1. TGF-beta 1 and RB appear to function in a common growth-inhibitory pathway in which TGF-beta 1 acts to retain RB in the underphosphorylated, growth-suppressive state.

Animals↗
PubMed1990

Cell-cell adhesion mediated by binding of membrane-anchored transforming growth factor alpha to epidermal growth factor receptors promotes cell proliferation.

The precursor for transforming growth factor alpha, pro-TGF-alpha, is a cell surface glycoprotein that can establish contact with epidermal growth factor (EGF) receptors on adjacent cells. To examine whether the pro-TGF-alpha/EGF receptor pair can simultaneously mediate cell adhesion and promote cell proliferation, we have expressed pro-TGF-alpha in a bone marrow stromal cell line. Expression of pro-TGF-alpha allows these cells to support long-term attachment of an EGF/interleukin-3-dependent hematopoietic progenitor cell line that expresses EGF receptors but is unable to adhere to normal stroma. This interaction is inhibited by soluble EGF receptor ligands. Further, the hematopoietic progenitor cells replicate their DNA while they are attached to the stromal cell layer and become foci of sustained cell proliferation. Thus, pro-TGF-alpha and the EGF receptor can function as mediators of intercellular adhesion and this interaction may promote a mitogenic response. We propose the term "juxtacrine" to designate this form of stimulation between adjacent cells.

Animals↗
PubMed1990

Transforming growth factor-beta receptors and binding proteoglycans.

Transforming growth factors-beta (TGFs-beta) are representative of a superfamily whose members were first identified as regulators of morphogenesis and differentiation, and subsequently found to be structurally related. Other members of the family include the activins and inhibins, BMPs, MIS, the DPP-C gene product and Vg-1. When assayed by affinity-labelling techniques, TGFs-beta bind to three distinct cell surface proteins which are present on most cells. These proteins are all of relatively low abundance but bind TGFs-beta with affinities consistent with the biological potency of the factors. The Type I and Type II binding proteins are glycoproteins with estimated molecular weights of 53 and 73 x 10(3) Mr, respectively. They both bind TGF-beta 1 significantly better than TGF-beta 2. The Type I receptor has been identified as the receptor which mediates many of the responses of TGFs-beta, based on somatic cell genetic studies of epithelial cell mutants unresponsive to TGFs-beta. Betaglycan is the third binding protein present on many, but not all, cell types and is a large proteoglycan (approximately 280 x 10(3) Mr) with 100-120 x 10(3) Mr core proteins. A soluble form of this molecule is present in conditioned media of many cell lines and may be derived from the cell surface-associated molecule by cleavage of a small membrane anchor. Betaglycan binds TGF-beta 1 and TGF-beta 2 with similar affinity and this binding is to the core proteins, not the glycosaminoglycan side chains. This molecule may have a function in the localization and delivery or the clearance of activated TGFs-beta.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗