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PubMed2001

Negative regulators of cyclin-dependent kinases and their roles in cancers.

In the past decade, the discovery and characterization of cyclin-dependent kinases (CDKs), the engine cores of the cell cycle machinery, have advanced our understanding of the cell cycle. Both positive and negative regulators of CDKs have been characterized, accelerating the important research to unravel the mechanisms of the cell cycle disease--cancer. Cancer can originate from overexpression of positive regulators, such as cyclins, or from underexpression of negative regulators, such as CDK inhibitors (CKIs). CKIs are the focus of much cancer research because they are capable of controlling cell cycle proliferation--the Holy Grail for cancer treatment. CDKs can be inactivated by several mechanisms:, (i) by association with CKIs including p16 (INK4a), p15 (INK4b), p21 (Cip1), p27 (Kip1), and p57 (Kip2), (ii) by disassociation from their cyclin regulatory unit, (iii) by dephosphorylation of a conserved threonine residue in the T-loop, and (iv) by adding inhibitory phosphate. Here we discuss what is known about each mechanism with a hope that these insights will become useful in developing strategies to eliminate cancer in the future.

14-3-3 Proteins↗
PubMed2000

Identification of an alpha-helical epitope region on the PM/Scl-100 autoantigen with structural homology to a region on the heterochromatin p25beta autoantigen using immobilized overlapping synthetic peptides.

The polymyositis-scleroderma overlap syndrome (PM/Scl) autoantigen is a nucleolar multiprotein particle, presumably participating in the maturation of 5.8S rRNAs. The major target antigens of this particle are two polypeptides with apparent molecular masses of 100 and 75 kDa. In this study we identified the major linear epitopes along the PM/Scl-100 protein sequence by probing overlapping oligopeptides with anti-PM/Scl autoantisera. A major epitope region was identified between amino acids 231 and 245 of the PM/Scl-100 polypeptide. Mutational analysis of the corresponding peptide LDVPPALADFIHQQR by glycine-walk followed by immunodetection of the resulting peptides indicated that amino acids 234, 237, 240, and 241 of the PM/Scl-100 autoantigen are essential for binding of the corresponding antibodies. These results allow us to propose a local alpha-helical secondary structure for the PM/Scl-100 major epitope region. A homology search with the peptide LDVPPALADFIHQQR against the Swiss-Model three-dimensional database reveals some topological homology of the PM/Scl-100 major epitope region with the heterochromatin modifier protein p25beta, a known autoantigen recognized by antibodies from a subset of scleroderma patients.

Amino Acid Sequence↗
PubMed2006

Identification of a new HLA-A*0201-restricted cytotoxic T lymphocyte epitope from CML28.

Identification of cytotoxic T lymphocyte (CTL) epitopes from additional tumor antigens is essential for the development of specific immunotherapy of malignant tumors. CML28, a recently discovered cancer-testis (CT) antigen from chronic myelogenous leukemia, is considered to be a promising target of tumor-specific immunotherapy. Because HLA-A*0201 is one of the most common histocompatibility molecule in Chinese, we aim at identifying CML28 peptides presented by HLA-A*0201. A panel of CML28-derived antigenic peptides was predicted using a computer-based program. Four peptides with highest predicted score were synthesized and tested for their binding affinities to HLA-A*0201 molecule. Then these peptides were assessed for their immunogenicity to elicit specific immune responses mediated by CTLs both in vitro, from PBMCs sourced from four healthy HLA-A*0201(+) donors, and in vivo, in HLA-A*0201 transgenic mice. One of the tested peptides, CML28((173-181)), induced peptide-specific CTLs in vitro as well as in vivo, which could specifically secrete IFN-gamma and lyse major histocompatibility complex (MHC)-matched tumor cell lines endogenously expressing CML28 antigen and CML28((173-181) )pulsed Jurkat-A2/Kb cells, respectively. These results demonstrate that CML28((173-181) )is a naturally processed and presented CTL epitope with HLA-A*0201 motif and has a promising immunogenicity both in vitro and in vivo. As CML28 is expressed in a large variety of histological tumors besides chronic myelogenous leukemia, we propose that the newly identified epitope, CML28((173-181)), would be of potential use in peptide-based, cancer-specific immunotherapy against a broad spectrum of tumors.

Amino Acid Sequence↗
PubMed2005

Gene overexpression in pancreatic adenocarcinoma: diagnostic and therapeutic implications.

Pancreatic cancer is the deadliest of cancers, and effective diagnostic and therapeutic strategies are lacking. Global gene expression profiling holds promise for improved diagnosis and treatment. Knowledge of the location and timing of gene overexpression and the function of these genes, including their effects on signaling pathways, is important. These data may be used to develop histologic and serum biomarkers as well as to develop immunotherapeutic, molecular targeting, and gene therapy strategies. We have compiled a list of overexpressed genes in pancreatic cancer for which overexpression was confirmed by reverse transcriptase polymerase chain reaction, immunohistochemistry, and/or in situ hybridization following initial identification by global gene expression profiling. The techniques used in the determination of overexpression, problems encountered in global gene expression profiling, and the diagnostic and therapeutic implications of overexpression are discussed. The S100 gene family, mesothelin, prostate stem cell antigen, and 14-3-3 sigma, may have important clinical implications in pancreatic cancer diagnosis and treatment.

14-3-3 Proteins↗
PubMed2005

A role for KEM1 at the START of the cell cycle in Saccharomyces cerevisiae.

KEM1 is a Saccharomyces cerevisiae gene, conserved in all eukaryotes, whose deletion leads to pleiotropic phenotypes. For the most part, these phenotypes are thought to arise from Kem1p's role in RNA turnover, because Kem1p is a major 5'-3' cytoplasmic exonuclease. For example, the exonuclease-dependent role of Kem1p is involved in the exit from mitosis, by degrading the mRNA of the mitotic cyclin CLB2. Here, we describe the identification of a KEM1 truncation, KEM1(1-975), that accelerated the G1 to S transition and initiation of DNA replication when over-expressed. Interestingly, although this truncated Kem1p lacked exonuclease activity, it could efficiently complement another function affected by the loss of KEM1, microtubule-dependent nuclear migration. Taken together, the results we report here suggest that Kem1p might have a previously unrecognized role at the G1 to S transition, but not through its exonuclease activity. Our findings also support the notion that Kem1p is a multifunctional protein with distinct and separable roles.

Cell Cycle Proteins↗
PubMed1996

Requirement of S. pombe exonuclease II, a homologue of S. cerevisiae Sep1, for normal mitotic growth and viability.

Exonuclease II (ExoII) from Schizosaccharomyces pombe is a 5'-->3' single-stranded DNA exonuclease. We have cloned its gene, exo2, whose nucleotide sequence revealed that ExoII is a homologue of the multifunctional Saccharomyces cerevisiae Sep1 protein (also called Kem1, Xrn1, Rar5, Dst2). S. pombe exo2 null mutants were cold-sensitive for growth, had increased cell size at the restrictive temperature, were hypersensitive to the mitotic inhibitor thiabendazol and to caffeine, and died rapidly in stationary phase. Many of these phenotypes are similar to those of sep1 (kem1 or xrn1) mutants of S. cerevisiae. In contrast, the exo2 mutation had only a moderate effect on progression through meiosis and no significant effect on meiotic recombination. We discuss possible functions of the multifunctional ExoII protein.

Amino Acid Sequence↗
PubMed1999

Cysteine uptake by Saccharomyces cerevisiae is accomplished by multiple permeases.

Uptake by Saccharomyces cerevisiae of the sulphur-containing amino acid L-cysteine was found to be non-saturable under various conditions, and uptake kinetics suggested the existence of two or more transport systems in addition to the general amino-acid permease, Gap1p. Overexpression studies identified BAP2, BAP3, AGP1 and GNP1 as genes encoding transporters of cysteine. Uptake studies with disruption mutants confirmed this, and identified two additional genes for transporters of cysteine, TAT1 and TAT2, both very homologous to BAP2, BAP3, AGP1 and GNP1. While Gap1p and Agp1p appear to be the main cysteine transporters on the non-repressing nitrogen source proline, Bap2p, Bap3p, Tat1p, Tat2p, Agp1p and Gnp1p are all important for cysteine uptake on ammonium-based medium. Furthermore, whereas Bap2p, Bap3p, Tat1p and Tat2p seem most important under amino acid-rich conditions, Agp1p contributes significantly when only ammonium is present, and Gnp1p only contributes under the latter condition.

ATP-Binding Cassette Transporters↗
PubMed1999

Substrate specificity and gene expression of the amino-acid permeases in Saccharomyces cerevisiae.

All known amino-acid permeases (AAPs) in Saccharomyces cerevisiae belong to a single family of homologous proteins. Genes of 15 AAPs were overexpressed in different strains, and the ability to take up one or more of the 20 common L-alpha-amino acids was studied in order to obtain a complete picture of the substrate specificity for these permeases. Radiolabelled amino-acid uptake measurements showed that Agp1p is a general permease for most uncharged amino acids (Ala, Gly, Ser, Thr, Cys, Met, Phe, Tyr, Ile, Leu, Val, Gln and Asn). Gnp1p, which is closely related to Agp1p, has a somewhat less-broad specificity, transporting Leu, Ser, Thr, Cys, Met, Gln and Asn, while Bap2p and Bap3p, which are also closely related to Agp1p, are able to transport Ile, Leu, Val, Cys, Met, Phe, Tyr and Trp. All four permeases are transcriptionally induced by an extracellular amino acid, but differ in expression with respect to the nitrogen source. On a non-repressive nitrogen source, AGP1 is induced, while GLN1, BAP2 and BAP3 are not. Except for Dip5p, which is a transporter for Glu, Asp, Gln, Asn, Ser, Ala and Gly, the rest of the permeases exhibit narrow specificity. Tat2p can take up Phe, Trp and Tyr; Put4p can transport Ala, Gly and Pro; while Can1p, Lyp1p and the previously uncharacterized Alp1p are specific for the cationic amino acids. These findings modify the prevalent view that S. cerevisiae only contains one general amino-acid permease, Gap1p, and a number of permeases that are specific for a single or a few amino acids.

Amino Acid Transport Systems↗
PubMed2005

[PM-Scl antibody positive systemic sclerosis associated with inclusion-body myositis].

We describe a 72- year-old patient with a ten year history of anti-PM-Scl positive systemic sclerosis associated with inclusion-body myositis. While the association of dermatomyositis and polymyositis with anti-PM-Scl positive systemic sclerosis is frequently reported, inclusion-body myositis was, to the best of our knowledge, only previously described once in association with anti-PM-Scl-positive systemic sclerosis. The distinction between inclusion-body myositis and other forms of inflammatory myopathy, like the histopathologically well distinguishable polymyositis or dermatomyositis, is relevant because of the poor response of inclusion- body myositis to immunosuppressive treatment. Our case underlines that in patients with anti-PM-Scl-positive systemic sclerosis and treatment resistant progressive myopathy the diagnosis of inclusion body myositis should be considered.

Aged↗
PubMed2006

p21WAF1/CIP1 and 14-3-3 sigma gene expression in degenerated aortic valves: a link between cell cycle checkpoints and calcification.

The mechanisms underlying aortic valve degeneration are largely unknown. Cardiac tissue responds to a variety of stimuli by hypertrophic growth. Molecular mechanisms resulting in the hypertrophic response indicate similarity and overlap with those involved in both cell growth and death. We hypothesized cell cycle control to be the key event in progression regulation of heart valve degeneration followed by tissue mineralization. Human post-operative tissue samples of native non-rheumatic stenosed aortic valves were categorized according to absence (group 1) or presence of calcification (group 2). The samples were ex vivo examined for cell density and presence of macrophage (CD68), as well as expression of two checkpoint genes, p21WAF1/CIP1 and 14-3-3 sigma, arresting the G1 and G2 cell cycle phases, respectively. Expression rates were measured by "Real-Time"-PCR on transcriptional level. Target protein expression was measured and their co-localization in different kinds of valvular cells was tested using immunohistochemical analysis. Whereas macrophages were localized predominantly in sub-endothelial layer of valvular fibrosis, p21WAF1/CIP1 and 14-3-3 sigma expression was observed also in the valvular spongiosa co-localized with alpha-actin positive cells. Significantly higher cell density and inflammation grade were observed in group 2 versus group 1. Accordingly, p21WAF1/CIP1 and 14-3-3 sigma expression was several fold higher in group 1 versus group 2 on both transcription and translation levels. The present findings on degenerated aortic valves show that increased cell density accompanied with consequent calcification might be attributed to the down-regulation of both G1 and G2 checkpoint genes.

14-3-3 Proteins↗
PubMed1983

Assay of 2',5'-oligoadenylate phosphodiesterase activity in mouse L-cell extracts.

A rapid and convenient assay for adenylyl(2' leads to 5')adenosine(A2'p5'A) or adenylyl(3' leads to 5')adenosine(A3'p5'A) phosphodiesterase activities is described. The dinucleotides A3'p5'A and A2'p5'A were labeled to a high specific activity by means of a catalytic-exchange procedure. Degradation studies of each of these labeled dinucleotides showed an asymmetrical distribution of label between the two adenine bases. Enzymatic degradation of [3H]A3'p5'A or [3H]A2'p5'A could be quantitated by first digesting the reaction products with bacterial alkaline phosphatase and then adding a slurry of DEAE-Sephadex. Under conditions described, adenosine did not adsorb to the resin, whereas dinucleotides as well as AMP did adsorb. As a consequence, when liquid scintillation fluid was added to the DEAE-Sephadex reaction mixture slurry, the radioactivity of the dinucleotides and AMP was severely quenched. This permitted a direct estimation of the amount of adenosine liberated during the phosphodiesterase degradation and subsequent alkaline phosphatase digestion. This method was applied to the measurement of A2'p5'A degrading activities in extracts of mouse L cells. Extracts from control mouse L cells were as active in degrading A2'p5'A as extracts from interferon pretreated cells.

Adenosine Monophosphate↗
PubMed1981

Heterogeneity of neutral ribonuclease II and ribonuclease II-inhibitor complex from mouse skeletal muscle.

Using either DEAE-cellulose chromatography or pH 4--6 isoelectric focusing, we have separated mouse skeletal muscle neutral RNAase II-inhibitor complex into two fractions (designated alph and beta). para-Hydroxymercuriphenyl-sulfonate-induced dissociation/inactivation of the inhibitor yields free RNAase II enzyme fractions with differing pH profiles, CM-cellulose chromatographic behavior and reactivity with the RNAase II inhibitor of human placenta. However, the free RNAase fractions react equally with purified inhibitor from skeletal muscle and are not separable by pH 8--9.5 isoelectric focusing. These data suggest that mouse skeletal muscle has two heterogeneous forms of RNAase II. Additionally, heterologous RNAase II inhibitors may be used as investigational tools when probing neutral RNAase II heterogeneity.

Animals↗
PubMed1984

Phenobarbital enhances 2',5'-oligoadenylate synthesis in rat liver nuclei.

Treatment of rats with phenobarbital for three days greatly increases the activity of 2,5 oligoadenylate synthetase in liver nuclei. Analysis of 2',5'-oligoadenylates synthesized in vitro showed that nuclei from both phenobarbital-treated and control rats synthesized 2',5'-oligoadenylates ranging from di- to hexamers. However, nuclei from drug treated rats showed a two fold increase in trimer and tetramer synthesis and a three-four fold increase in longer chained oligoadenylates. There was no change in the nuclear 2'-phosphodiesterase activity as the result of phenobarbital treatment, This activity remained low in nuclei from either the treated or the control rats. To our knowledge, this is the first report on phenobarbital affecting the liver 2',5'-oligoadenylate system.

2',5'-Oligoadenylate Synthetase↗
PubMed1985

Activities of cAMP-dependent protein kinase and enzymes of 2',5'-oligoadenylate metabolism in NIH 3T3 cells deepening into the resting state.

The activity of cAMP-dependent protein kinase was found to increase continuously in the NIH 3T3 cells, deepening into the resting state. The increase correlated with intracellular level of heat-stable protein inhibitor of the protein kinase rather than with the cAMP content. The elevation of 2',5'-oligo(A) synthetase activity and the decrease in 2'-phosphodiesterase activity were also observed in the cells sinking into the resting state. The variations in enzyme activities were similar to those caused by the increase in the intracellular cAMP content described elsewhere. These results agree with the idea that the cAMP-dependent protein kinase is involved in the regulation of the enzymes of 2',5'-oligo(A) metabolism.

2',5'-Oligoadenylate Synthetase↗
PubMed1986

Nerve growth factor induces changes in (2'-5')oligo(A) synthetase and 2'-phosphodiesterase activities during differentiation of PC12 pheochromocytoma cells.

Treatment of rat pheochromocytoma cell line PC12 with Vipera lebetina (snake) nerve growth factor (NGF) induces a rapid increase (from 5 to 25-fold) in the level of (2'-5')oligo(A) synthetase activity and a simultaneous decrease (from 2 to 5-fold) in the activity of 2'-5' A degrading enzymes--2'-phosphodiesterases (2'-PDE). These changes in the enzyme activities led to the significant increase in the intracellular concentration of 2'-5' A. We have found that the serum starvation of PC12 cells causes a 1.5 to 2.0-fold increase in the level of 2'-5' A-synthetase activity, but the activities of 2'-PDE and the intracellular concentration of 2'-5' A remain unaltered. These results show that NGF modulates the activity of (2'-5')oligo(A) enzymes and intracellular concentration of 2'-5' A during the neural differentiation of PC12 cells.

2',5'-Oligoadenylate Synthetase↗