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At least 505 records · Page 28Linked to original sources
PubMed2001

Aberrant expression of cell-cycle regulatory proteins in human mesenchymal neoplasia.

We previously demonstrated that approximately one-half of soft-tissue sarcomas were devoid of either pRB, the product of the retinoblastoma gene, or 16, the product of the MTS1/CDKN2 gene, while a smaller subset of aggressive mesenchymal tumors without metastatic potential did not express RB by immunohistochemistry. We now studied the expression of two additional important cell-cycle regulators, namely cyclin D1 and p53, in the same cohort of high- and low-grade lesions. In the aggregate, our data provide a comprehensive overview of the importance of cell-cycle deregulation in mesenchymal neoplasia. Paraffin sections of 58 sarcomas and 23 soft-tissue tumors of low malignant potential (STT-LMP) were reacted with monoclonal antibodies against cyclin D1 and p53, using optimized immunohistochemical staining protocols. The staining data were correlated with expression of pRB and p15 and with a variety of pathologic parameters. A total of 33 of 58 sarcomas (57%) and 9 of 23 STT-LMP (39%) overexpressed p53. Fourteen sarcomas (24%) and 4 STT-LMP (17%) overexpressed cyclin D1. There was no correlation between expression of these two genes and histologic tumor type or grade. Loss of RB and loss of p16 or overexpression of cyclin D1 were mutually exclusive events. Considering all four cell-cycle regulators, sarcomas had a significantly higher abnormality rate than did STT-LMP (P < .005). Only 10% of the sarcomas but 39% of STT-LMP showed normal expression of all four gene products. Based on our findings, overexpression of cyclin D1 and (presumably mutant) p53 appear to be among the most common molecular alterations in human mesenchymal neoplasia, and abrogation of cell-cycle control is observed in the great majority of sarcomas; it is present significantly less frequently in low-grade lesions.

Cell Cycle↗
PubMed2006

Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch.

Pleiotropism is a hallmark of cytokines and growth factors; yet, the underlying mechanisms are not clearly understood. We have identified a motif in the granulocyte macrophage-colony-stimulating factor receptor composed of a tyrosine and a serine residue that functions as a binary switch for the independent regulation of multiple biological activities. Signalling occurs either through Ser585 at lower cytokine concentrations, leading to cell survival only, or through Tyr577 at higher cytokine concentrations, leading to cell survival as well as proliferation, differentiation or functional activation. The phosphorylation of Ser585 and Tyr577 is mutually exclusive and occurs via a unidirectional mechanism that involves protein kinase A and tyrosine kinases, respectively, and is deregulated in at least some leukemias. We have identified similar Tyr/Ser motifs in other cell surface receptors, suggesting that such signalling switches may play important roles in generating specificity and pleiotropy in other biological systems.

14-3-3 Proteins↗
PubMed2004

The binding of kappa-Conotoxin PVIIA and fast C-type inactivation of Shaker K+ channels are mutually exclusive.

Kappa-conotoxin PVIIA (kappa-PVIIA), a 27-amino acid peptide identified from the venom of Conus purpurascens, inhibits the Shaker K+ channel by blocking its outer pore. The toxin appears as a gating modifier because its binding affinity decreases with relatively fast kinetics upon channel opening, but there is no indication that it interferes with the gating transitions of the wild-type channels (WT), including the structural changes of the outer pore that underlie its slow C-type inactivation. In this report we demonstrate that in two outer pore mutants of Shaker-IR (M448K and T449S), that have high toxin sensitivity and fast C-type inactivation, the latter process is instead antagonized by and incompatible with kappa-PVIIA binding. Inactivation is slowed by the necessary preliminary unbinding of kappa-PVIIA, whereas toxin rebinding must await recovery from inactivation causing a double-exponential relaxation of the second response to double-pulse stimulations. Compared with the lack of similar effects in WT, these results demonstrate the ability of peptide toxins like kappa-PVIIA to reveal possibly subtle differences in structural changes of the outer pore of K+ channels; however, they also warn against a naive use of fast inactivating mutants as models for C-type inactivation. Unfolded from the antagonistic effect of inactivation, toxin binding to mutant noninactivated channels shows state- and voltage-dependencies similar to WT: slow and high affinity for closed channels; relatively fast dissociation from open channels at rate increasing with voltage. This supports the idea that these properties depend mainly on interactions with pore-permeation processes that are not affected by the mutations. In mutant channels the state-dependence also greatly enhances the protection of toxin binding against steady-state inactivation at low depolarizations while still allowing large responses to depolarizing pulses that relieve toxin block. Although not obviously applicable to any known combination of natural channel and outer-pore blocker, our biophysical characterization of such highly efficient mechanism of protection from steady-state outer-pore inactivation may be of general interest.

Animals↗
PubMed2004

Neighbour joining trees, dominant markers and population genetic structure.

Population genetic theory for 'traditional' codominant loci showing low levels of allelic diversity (eg allozymes) has been well characterised and evaluated. In contrast, appropriate methods for the analysis of data from more recently developed marker systems are still being refined. For multilocus dominant markers such as amplified fragment length polymorphisms (AFLPs) and randomly amplified polymorphic DNA (RAPDs), the methods of data analysis can be split into two main categories. In population-based approaches, population allele frequencies are compared to obtain some measure of the partitioning of genetic diversity into within- and between-population components. In contrast, individual-based approaches use individual multilocus genotypes as the unit of analysis. Inferences on population processes such as gene flow are based on inter-relationships among individual samples as visualised on phenetic diagrams such as neighbour joining trees. Using a simulation approach coupled with neighbour joining analyses, we show that while the underlying population genetic structure is an important determinant of tree shape in the analysis of dominant data, the number of loci examined also affects the topology. At low levels of population differentiation (eg FST=0.07), mutually exclusive clustering of individuals into their respective populations can occur when sufficiently large numbers of loci are scored (eg 250 loci, typical of many AFLP studies). In contrast, unresolved star-shaped topologies can be recovered at higher levels of population differentiation (FST= >0.15) when lower numbers of loci are employed (eg 50 loci, typical of many RAPD studies). Thus, the relationship between tree topology and the extent of genetic structuring of populations is contingent upon the number of dominant loci scored. The consequences of these findings for the biological interpretation of individual-based analysis of dominant data sets are discussed.

Alleles↗
PubMed2000

The use of mutants to probe models of gravitropism.

It has been widely believed for more than 70 years that auxin plays a central role in the induction of differential growth which causes gravitropic curvature. However, this long-standing consensus about a role for auxin in gravitropism has only been achieved by allowing several mutually exclusive models to coexist. Furthermore, because there is no detailed model which is unchallenged by evidence, consensus is now centred on ill-defined models which have a low predictive value, hence are harder to challenge experimentally. An increasing number of mutants with abnormal gravitropic behaviour are becoming available. Such mutants should be very helpful in challenging existing models of gravitropism and in providing new evidence on which to build improved, more precise models. However, to date, most studies of mutants with abnormal gravitropism have been guided, experimentally and conceptually, by the old inadequate and vague models. Consequently, the full potential of modern molecular analysis in aiding our understanding of gravitropism has yet to be realized.

Gravitropism↗
PubMed1997

BCL-6 protein expression in AIDS-related non-Hodgkin's lymphomas: inverse relationship with Epstein-Barr virus-encoded latent membrane protein-1 expression.

This study aimed at investigating the expression of the BCL-6 protein in acquired immune deficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHLs) and at comparing the expression pattern with the presence of Epstein-Barr virus (EBV) infection of the tumor clone. A total of 34 AIDS-NHL biopsies, including 16 AIDS-related diffuse large-cell lymphomas (AIDS-DLCLs) and 18 AIDS-related small-noncleaved-cell lymphomas (AIDS-SNCCLs) as well as 7 AIDS-SNCCL cell lines were immunostained with a BCL-6-specific monoclonal antibody. Expression of BCL-6 protein was detected in 9 of 16 AIDS-DLCLs, 18 of 18 AIDS-SNCCLs, and 3 of 7 AIDS-SNCCL cell lines. Expression of BCL-6 among AIDS-NHLs occurred independently of the presence of molecular lesions of the bcl-6 gene. Notably, among EBV-positive AIDS-NHL biopsies and cell lines, expression of BCL-6 was mutually exclusive with the expression of EBV-encoded transforming antigen latent membrane protein-1. The mutual exclusion between BCL-6 and latent membrane protein-1 expression was further confirmed by in vitro superinfection experiments of an AIDS-SNCCL cell line originally devoid of EBV sequences. Overall, the frequent association between AIDS-NHLs and expression of BCL-6, a protein selectively expressed by germinal center B cells, suggests that these lymphomas may originate from the germinal center.

Acquired Immunodeficiency Syndrome↗
PubMed1988

A simple method of distinguishing the bacterial viruses T3 and T7, and a critical reevaluation of their heterologous and homologous exclusion.

A method is presented allowing a clear distinction between bacterial viruses T3 and T7 by plating on selectively permissive host cells. The indicator strains are Escherichia coli cells containing either cloned pif genes (exclusively permissive for T3) or the EcoRV DNA restriction system (permissive only for T7): The efficiencies of plating of the two phages on these hosts differ by more than 8 orders of magnitude. This method was applied to reinvestigate the controversial question of mutual exclusion between T3 and T7. Under single-burst conditions, about 50% of coinfected cells (permissive for both viruses) produced T3 and T7 progeny while about 25% reproduced only T3 and about 25% only T7. The burst size of co-infected cells was slightly reduced, compared to controls infected with only one virus type. Homologous exclusion among T3 phages was also not seen; rather, there was a gene dosage effect: T3-encoded RNA polymerase activity as well as T3-specific RNA synthesis increased proportionally to the multiplicity of infection (2.5-20 plaque-forming units/cell).

DNA Restriction Enzymes↗
PubMed1998

Developmentally regulated muscle type-specific alternative splicing of the COOH-terminal variable region of fast skeletal muscle troponin T and an aberrant splicing pathway to encode a mutant COOH-terminus.

Distinct from the cardiac and slow skeletal muscle troponin Ts, an alternative RNA splicing-generated COOH-terminal variable region exists in the fast skeletal muscle troponin T. Mutually exclusive splicing of exon 16 and 17 encoded sequence into the mature mRNA produces the alpha- and beta-isoform, respectively. By cloning and sequence analysis of large numbers of fast troponin T cDNAs, we have quantitatively demonstrated that expression of the exon 16-encoded structure is mature fast muscle-specific (its utilization ranges from null in neonatal mouse muscles to 97% in adult chicken pectoralis), indicating a functional adaptation to the contractile feature of muscle. An aberrant splicing of this variable region to exclude both exons 16 and 17 from the mRNA was found in neonatal mouse skeletal muscle by cloning and sequencing characterization of a full length fTnT cDNA. The unusual splicing of exon 18 and exon 15 in the mRNA sequence results in not only a deletion of the exon 16/17 segment but also a shift of the downstream translation reading frame to produce a troponin T polypeptide with mutant COOH-terminus. Similar to an abnormal splicing of cardiac troponin T caused by cis-mutation and a dominant allele causing human familial hypertrophic cardiomyopathy, this trans-factor-determined aberrant mRNA splicing pathway generates a truncated troponin T molecule lacking the developmentally regulated fast muscle-specific COOH-terminal domain, indicating potential etiopathological significance.

Amino Acid Sequence↗
PubMed1997

Over-expression of the chondroitin sulphate proteoglycan versican is associated with defective neural crest migration in the Pax3 mutant mouse (splotch).

Splotch mice, which harbour mutations in the Pax3 gene, exhibit neural crest-related abnormalities including pigmentation defects, reduced or absent dorsal root ganglia and failure of cardiac outflow tract septation in homozygotes. Although splotch neural crest cells fail to colonise target tissues, they initiate migration in vivo and appear to migrate as well as wild type neural crest cells in vitro, suggesting that the neural crest abnormality in splotch may reside not in the neural crest cells themselves, but rather in the extracellular environment through which they migrate. We have examined the expression of genes encoding extracellular matrix molecules in Sp2H homozygous embryos and find a marked over-expression of transcripts for the chondroitin sulphate proteoglycan versican in the pathways of neural crest cell migration. Use of cadherin-6 expression as a marker for neural crest demonstrates a striking correlation between up-regulation of versican expression and absence of migrating neural crest cells, both in the mesenchyme lateral to the neural tube and in the lower branchial arches of Sp2H homozygotes. Pax3 and versican have mutually exclusive expression patterns in normal embryos whereas, in Sp2H homozygotes, versican is generally over-expressed with 'infilling' in regions that would normally express functional Pax3. Versican, like other chondroitin sulphate proteoglycans, is non-permissive for migration of neural crest cells in vitro, and we suggest that over-expression of this molecule leads to the arrest of neural crest cell migration in splotch embryos. Pax3 may serve to negatively regulate versican expression during normal development, thereby guiding neural crest cells into their pathways of migration.

Animals↗
PubMed2000

Somatic hypermutation in MutS homologue (MSH)3-, MSH6-, and MSH3/MSH6-deficient mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base substitution pattern.

Although the primary function of the DNA mismatch repair (MMR) system is to identify and correct base mismatches that have been erroneously introduced during DNA replication, recent studies have further implicated several MMR components in somatic hypermutation of immunoglobulin (Ig) genes. We studied the immune response in mice deficient in MutS homologue (MSH)3 and MSH6, two mutually exclusive partners of MSH2 that have not been examined previously for their role in Ig hypermutation. In Msh6(-)/- and Msh3(-)/-/Msh6(-)/- mice, base substitutions are preferentially targeted to G and C nucleotides and to an RGYW hot spot, as has been shown previously in Msh2(-)/- mice. In contrast, Msh3(-)/- mice show no differences from their littermate controls. These findings indicate that the MSH2-MSH6 heterodimer, but not the MSH2-MSH3 complex, is responsible for modulating Ig hypermutation.

Adenosine Triphosphatases↗
PubMed2006

Transgenic alternative-splicing reporters reveal tissue-specific expression profiles and regulation mechanisms in vivo.

Alternative splicing of pre-mRNAs allows multicellular organisms to create a huge diversity of proteomes from a finite number of genes. But extensive studies in vitro or in cultured cells have not fully explained the regulation mechanisms of tissue-specific or developmentally regulated alternative splicing in living organisms. Here we report a transgenic reporter system that allows visualization of expression profiles of mutually exclusive exons in Caenorhabditis elegans. Reporters for egl-15 exons 5A and 5B showed tissue-specific profiles, and we isolated mutants defective in the tissue specificity. We identified alternative-splicing defective-1 (asd-1), encoding a new RNA-binding protein of the evolutionarily conserved Fox-1 family, as a regulator of the egl-15 reporter. Furthermore, an asd-1;fox-1 double mutant was defective in the expression of endogenous egl-15 (5A) and phenocopied egl-15 (5A) mutant. This transgenic reporter system can be a powerful experimental tool for the comprehensive study of expression profiles and regulation mechanisms of alternative splicing in metazoans.

Alternative Splicing↗
PubMed1996

Alternative splicing of the pyruvate kinase M gene in a minigene system.

The M1-type and M2-type isozymes of pyruvate kinase are produced from a single gene by mutually exclusive use of exons 9 and 10. Selection of exon 10 generates the M2 type, which occurs in most tissues, whereas the M1 type is expressed by use of exon 9 only in skeletal muscle, heart and brain. We investigated the mechanism by which exon 10, but not exon 9 is selected in M2-expressing cells by transfecting minigenes containing exon 9 and/or exon 10 in cells and by analyzing the transcripts using reverse-transcriptase polymerase chain reaction. Deletion of the most conserved region in intron 8 did not affect selection of exon 10 in dRLh-84 cells, which express only the M2 type. Exclusion of exon 10 from the minigene resulted in two major spliced products. One included correctly spliced exon 9 and the other skipped this exon. Similar splicing patterns were observed when these minigenes were transfected in hepatocytes which express the L type, but not M1 or M2 types. The 5' splice site but not the 3' splice site of exon 9 was found to be hardly recognized by the splicing machinery in dRLh-84 cells. Mutation of the 5' splice site sequence of exon 9 to that of exon 10 and vice versa did not change the splicing patterns. However, mutation of this site of exon 9 to a perfectly complementary sequence of U1 snRNA resulted in selection of exon 9 correctly spliced to exon 10. A 9-10 fusion exon (constructed by substitution of 68 bases of the 3' portion of exon 9 and 33 bases of the 5' portion of intron 9 for the corresponding regions of exon 10 and intron 10) was also correctly incorporated into a major product together with exon 10. Thus, we propose that exon 9 is not recognized in non M1-expressing cells due to the weak signal of its 5' splice site and that, although the 5' splicing signal of exon 10 also appears to be weak, this exon can be recognized in these cells because the 5' recognition signal may be relatively strengthened by cis-acting element(s) which may be present in the 3' portion of exon 9 and the 5' portion of intron 9 and/or the corresponding regions of exon 10 and intron 10.

Alternative Splicing↗
PubMed2003

Delineation of the regulated Variant Surface Glycoprotein gene expression site domain of Trypanosoma brucei.

The African trypanosome Trypanosoma brucei is protected in the bloodstream of the mammalian host by a dense Variant Surface Glycoprotein (VSG) coat. Although an individual cell has hundreds of VSG genes, the active VSG is transcribed in a mutually exclusive fashion from one of about twenty telomeric VSG expression sites. Expression sites are regulated domains flanked by 50 bp repeat arrays and extensive tracts of repetitive elements. We have integrated exogenous rDNA and expression site promoters upstream of the 50 bp repeats of the VO2 VSG expression site. Transcription from both types of exogenous promoter is downregulated and comparable to promoters targeted into the VSG Basic Copy arrays. We show that the upstream exogenous rDNA promoter escapes VSG expression site control, as switching the downstream VO2 VSG expression site on and off does not affect its activity. Therefore, the 50 bp repeat arrays appear to be the boundary of the regulated expression site domain.

Animals↗
PubMed2006

Structure and activation mechanism of the Drosophila initiator caspase Dronc.

Activation of an initiator caspase is essential to the execution of apoptosis. The molecular mechanisms by which initiator caspases are activated remain poorly understood. Here we demonstrate that the autocatalytic cleavage of Dronc, an important initiator caspase in Drosophila, results in a drastic enhancement of its catalytic activity in vitro. The autocleaved Dronc forms a homodimer, whereas the uncleaved Dronc zymogen exists exclusively as a monomer. Thus the autocatalytic cleavage in Dronc induces its stable dimerization, which presumably allows the two adjacent monomers to mutually stabilize their active sites, leading to activation. Crystal structure of a prodomain-deleted Dronc zymogen, determined at 2.5 A resolution, reveals an unproductive conformation at the active site, which is consistent with the observation that the zymogen remains catalytically inactive. This study revealed insights into mechanism of Dronc activation, and in conjunction with other observations, suggests diverse mechanisms for the activation of initiator caspases.

Amino Acid Sequence↗
PubMed2006

Shigella applies molecular mimicry to subvert vinculin and invade host cells.

Shigella flexneri, the causative agent of bacillary dysentery, injects invasin proteins through a type III secretion apparatus upon contacting the host cell, which triggers pathogen internalization. The invasin IpaA is essential for S. flexneri pathogenesis and binds to the cytoskeletal protein vinculin to facilitate host cell entry. We report that IpaA harbors two vinculin-binding sites (VBSs) within its C-terminal domain that bind to and activate vinculin in a mutually exclusive fashion. Only the highest affinity C-terminal IpaA VBS is necessary for efficient entry and cell-cell spread of S. flexneri, whereas the lower affinity VBS appears to contribute to vinculin recruitment at entry foci of the pathogen. Finally, the crystal structures of vinculin in complex with the VBSs of IpaA reveal the mechanism by which IpaA subverts vinculin's functions, where S. flexneri utilizes a remarkable level of molecular mimicry of the talin-vinculin interaction to activate vinculin. Mimicry of vinculin's interactions may therefore be a general mechanism applied by pathogens to infect the host cell.

Actins↗
PubMed2006

Scanning peptide array analyses identify overlapping binding sites for the signalling scaffold proteins, beta-arrestin and RACK1, in cAMP-specific phosphodiesterase PDE4D5.

The cAMP-specific phosphodiesterase PDE4D5 can interact with the signalling scaffold proteins RACK (receptors for activated C-kinase) 1 and beta-arrestin. Two-hybrid and co-immunoprecipitation analyses showed that RACK1 and beta-arrestin interact with PDE4D5 in a mutually exclusive manner. Overlay studies with PDE4D5 scanning peptide array libraries showed that RACK1 and beta-arrestin interact at overlapping sites within the unique N-terminal region of PDE4D5 and at distinct sites within the conserved PDE4 catalytic domain. Screening scanning alanine substitution peptide arrays, coupled with mutagenesis and truncation studies, allowed definition of RACK1 and beta-arrestin interaction sites. Modelled on the PDE4D catalytic domain, these form distinct well-defined surface-exposed patches on helices-15-16, for RACK1, and helix-17 for beta-arrestin. siRNA (small interfering RNA)-mediated knockdown of RACK1 in HEK-293 (human embryonic kidney) B2 cells increased beta-arrestin-scaffolded PDE4D5 approx. 5-fold, increased PDE4D5 recruited to the beta2AR (beta2-adrenergic receptor) upon isoproterenol challenge approx. 4-fold and severely attenuated (approx. 4-5 fold) both isoproterenol-stimulated PKA (protein kinase A) phosphorylation of the beta2AR and activation of ERK (extracellular-signal-regulated kinase). The ability of a catalytically inactive form of PDE4D5 to exert a dominant negative effect in amplifying isoproterenol-stimulated ERK activation was ablated by a mutation that blocked the interaction of PDE4D5 with beta-arrestin. In the present study, we show that the signalling scaffold proteins RACK1 and beta-arrestin compete to sequester distinct 'pools' of PDE4D5. In this fashion, alterations in the level of RACK1 expression may act to modulate signal transduction mediated by the beta2AR.

Amino Acid Sequence↗
PubMed1997

Glutathione reductase turned into trypanothione reductase: structural analysis of an engineered change in substrate specificity.

Trypanosoma and Leishmania, pathogens responsible for diseases such as African sleeping sickness, Chagas' heart disease, or Oriental sore, are two of the very few genera that do not use the ubiquitous glutathione/glutathione reductase system to keep a stable cellular redox balance. Instead, they rely on trypanothione and trypanothione reductase to protect them from oxidative stress. Trypanothione reductase (TR) and the corresponding host enzyme, human red blood cell glutathione reductase (GR), belong to the same flavoprotein family. Despite their closely related three-dimensional structures and although their natural substrates share the common structural glutathione core, the two enzymes are mutually exclusive with respect to their disulfide substrates. This makes the parasite enzyme a potential target for antitrypanosomal drug design. While a large body of structural data on GR complexes is available, information on TR-ligand interactions is very limited. When the two amino acid changes Ala34Glu and Arg37Trp are introduced into human GR, the resulting mutant enzyme (GRTR) prefers trypanothione 700-fold over its original substrate, effectively converting a GR into a TR [Bradley, M., Bücheler, U. S., & Walsh, C. T. (1991) Biochemistry 30, 6124-6127]. The crystal structure of GRTR has been determined at 2.3 A resolution and refined to a crystallographic R factor of 20.9%. We have taken advantage of the ease with which ligand complexes can be produced in GR crystals, a property that extends to the isomorphous GRTR crystals, and have produced and analyzed crystals of GRTR complexes with glutathione, trypanothione, glutathionylspermidine and of a true catalytic intermediate, the mixed disulfide between trypanothione and the enzyme. The corresponding molecular structures have been characterized at resolutions between 2.3 and 2.8 A with R factors ranging from 17.1 to 19.7%. The results indicate that the Ala34Glu mutation causes steric hindrance leading to a large displacement of the side chain of Arg347. This movement combined with the change in charge introduced by the mutations modifies the binding cavity, forcing glutathione to adopt a nonproductive binding mode and permitting trypanothione and to a certain degree also the weak substrate glutathionylspermidine to assume a productive mode.

Animals↗
PubMed2003

Epigenetic inactivation of the Ras-association domain family 1 (RASSF1A) gene and its function in human carcinogenesis.

The Ras GTPases are a superfamily of molecular switches that regulate cellular proliferation and apoptosis in response to extra-cellular signals. The regulation of these pathways depends on the interaction of the GTPases with specific effectors. Recently, we have cloned and characterized a novel gene encoding a putative Ras effector: the Ras-association domain family 1 (RASSF1) gene. The RASSF1 gene is located in the chromosomal segment of 3p21.3. The high allelic loss in a variety of cancers suggested a crucial role of this region in tumorigenesis. At least two forms of RASSF1 are present in normal human cells. The RASSF1A isoform is highly epigenetically inactivated in lung, breast, ovarian, kidney, prostate, thyroid and several other carcinomas. Re-expression of RASSF1A reduced the growth of human cancer cells supporting a role for RASSF1 as a tumor suppressor gene. RASSF1A inactivation and K-ras activation are mutually exclusive events in the development of certain carcinomas. This observation could further pinpoint the function of RASSF1A as a negative effector of Ras in a pro-apoptotic signaling pathway. In malignant mesothelioma and gastric cancer RASSF1A methylation is associated with virus infection of SV40 and EBV, respectively, and suggests a causal relationship between viral infection and progressive RASSF1A methylation in carcinogenesis. Furthermore, a significant correlation between RASSF1A methylation and impaired lung cancer patient survival was reported, and RASSF1A silencing was correlated with several parameters of poor prognosis and advanced tumor stage (e.g. poor differentiation, aggressiveness, and invasion). Thus, RASSF1A methylation could serve as a useful marker for the prognosis of cancer patients and could become important in early detection of cancer.

Animals↗