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PubMed2005

[Sequence and structure analysis of cryptic plasmid pN30 from oil-oxidizing strain Rhodococcus erythropolis 30].

Nucleotide sequence of cryptic plasmid pN30 from a Rhodococcus erythropolis 30 soil isolate was determined. Plasmid DNA consists of 5403 nucleotide pairs and contains about 62% GC pairs, which is typical of Rhodococcus DNA. No significant homology was determined between the pN30 DNA sequence and those of known plasmids. Computer-aided analysis of pN30 sequence revealed open reading frames that encode proteins strongly homologous to replicative proteins encoded by small cryptic plasmids of different actinomycetes.

Amino Acid Sequence↗
PubMed2002

Tales of the cryptic: unveiling more angiogenesis inhibitors.

Over the past few years, there has been a dramatic increase in the identification of anti-angiogenic fragments from larger proteins with unrelated functions. These cryptic anti-angiogenic molecules are largely derived from matrix components such as collagen and fibronectin, as well as from circulating proteins and some intracellular proteins. Here, we discuss the relevance of these developments in terms of their physiological roles and possible therapeutic applications.

Angiogenesis Inhibitors↗
PubMed1980

Pituitary immunoreactive gamma-melanotropins are glycosylated oligopeptides.

Nakanishi et al. have recently characterised the complete sequence of the mRNA isolated from the intermediate lobe of bovine pituitary which codes for the 31,000 molecular weight (31K) precursor protein of corticotropin/beta-lipotropin (ACTH/beta-LPH). The corresponding amino acid sequence translated from this mRNA revealed in the cryptic region of the precursor protein a fragment sharing a common amino acid sequence with the alpha- beta-melanotropins (alpha-MSH, beta-MSH) and thus named gamma-MSH. To study whether this gamma-MSH fragment is also processed and released as a biologically active substance and to ascertain its location in the pituitary and possibly in the brain, we have raised antibodies to the synthetic replicate of gamma 3-MSH (ref. 2). We report here the detection of at least two gamma-MSH-like peptides in the pituitary using these antibodies in a radioimmunoassay (RLA) and, furthermore, evidence that these two peptides are glycosylated.

Carbohydrate Metabolism↗
PubMed1994

Failure of presented, non-dominant self epitope to induce tolerance: implications for autoimmune diseases.

It has been observed that a hierarchy exists among epitopes such that fewer epitopes are actually involved in the induction of T cell response and tolerance than there are epitopes available in a given antigen. Some epitopes which are "cryptic" for immune activity within the protein, are nevertheless able to elicit a response if administered alone and can also be used to by-pass tolerance. We report that tolerance to a self protein shows the same phenomenon seen for non self proteins. In fact, we elicit a proliferative response toward a predicted minor cryptic epitope, to which animals are clearly not self-tolerant. The minor epitope escapes the induction of tolerance to self proteins more easily than the major epitopes, since we cannot elicit proliferative response to the major epitope. A striking feature of our results however is that lack of self tolerance to the minor epitope appears as not being due to the failure of presentation of this epitope in normal, healthy animals.

Animals↗
PubMed1993

Cell and heparin binding in the distal long arm of laminin: identification of active and cryptic sites with recombinant and hybrid glycoprotein.

The long arm of laminin, which binds heparin and cells, consists of three polypeptides (A, B1, and B2) joined in a coiled-coil rod attached to a terminal A chain globule (G). Previously, we found that recombinant globular domain (rG) supported heparin and myoblast binding (Yurchenco, P. D., U. Sung, M. D. Ward, Y. Yamada, and J. J. O'Rear. 1993. J. Biol. Chem. 268:8356-8365). To further analyze long arm functions, we expressed the distal moiety of the mouse laminin A chain extending from the middle of the rod to the carboxyl terminus (rAiG). This larger glycoprotein, secreted by Sf9 insect cells infected with recombinant baculovirus, was intercalated in vitro into the corresponding disulfide-linked B chain segments of laminin fragment E8 (distal long arm rod and proximal globule). The hybrid molecule (B-rAiG) possessed a structure similar to laminin long arm as judged by electron microscopy and limited proteolysis. By joining rAiG with E8-B chains, the affinity of G domain for heparin decreased from that observed with rAiG and rG to one similar to native protein. HT1080 cells adhered to E8, rAiG, and B-rAiG, less well to rG, and not to denatured E8/B-rAiG, the A and B chain moieties of E8, or to a mixture of rG and E8-B chains. Cell adhesion to E8 and B-rAiG, in contrast to rAiG, was inhibited with antibodies specific for alpha 6 and beta 1 integrin chains. Since intercalation (a) restored a conformationally dependent alpha 6 beta 1 integrin recognition site present in native protein, (b) inactivated a cryptic cell binding activity in the A chain, and (c) inhibited a heparin binding site present in proximal G domain, we conclude that biological activities of laminin are different from that of its isolated subunits.

Animals↗
PubMed2003

Functional cloning of drug resistance genes from retroviral cDNA libraries.

To improve the curative success of chemotherapy, it will be essential to understand the molecular basis of drug resistance (DR) and sensitivity. We have developed a cell culture system that enables the functional cloning of mammalian DR genes based on phenotypic selection after overexpression of mammalian retroviral cDNA libraries and validated our system using the anticancer drug cisplatin. ERCC1-deficient and therefore cisplatin-hypersensitive mouse embryonic fibroblast target cells were transduced with a human placenta retroviral cDNA library. Subsequent cisplatin selection yielded 20 DR clones, each containing a recurring human ERCC1 gene. Surprisingly, nine of these clones contained 5'-truncated ERCC1 sequences that required alternative splicing of the vector sequence to encode a functional ERCC1 protein. The usage of cryptic splice sites in the vector sequence should be taken into consideration when interpreting results from retroviral gene expression applications, and might have consequences for the safe application of retroviral constructs in gene therapy.

Alternative Splicing↗
PubMed2005

Novel intermediate of Rac GTPase activation by guanine nucleotide exchange factor.

The biochemical role of guanine nucleotide exchange factors (GEFs) in catalyzing small GTPase GDP-GTP exchange is thought to be twofold: stimulation of GDP dissociation and stabilization of a nucleotide-free GTPase intermediate. Here we report that TrioN, a Dbl family GEF, activates Rac1 by facilitating GTP binding to, as well as stimulating GDP dissociation from, Rac1. The TrioN-catalyzed GDP dissociation is dependent upon the structural nature and the concentration of free nucleotide, and nucleotide binding serves as the rate-limiting step of the GEF reaction. The TrioN-stimulated nucleotide exchange may undergo a novel two nucleotide-one G-protein intermediate involving two cryptic subsites on Rac1 induced by the GEF, with one subsite contributing to the recognition of the beta/gamma phosphates of the incoming GTP and another to the binding of the guanine base of the leaving GDP. We propose that the Rac GEF reaction may proceed by competitive displacement of bound GDP by GTP through a transient intermediate of GEF-[GTP-Rac-GDP].

Amino Acid Motifs↗
PubMed1996

Antiphospholipid antibodies and atherosclerosis.

The family of antiphospholipid antibodies includes antibodies binding to cardiolipin in serological test for syphilis, antibodies prolonging the clotting time in lupus anticoagulant test, antibodies reacting with plasma phospholipid-binding proteins, such as beta 2-glycoprotein I and prothrombin, and antibodies binding to oxidized low-density lipoprotein (LDL). Antiphospholipid antibodies are traditionally associated with arterial and venous thrombosis in patients with primary or secondary antiphospholipid syndrome. The recent studies, especially those on patients with myocardial infarction, extend the concept of antiphospholipid antibodies, and suggest that they play a role also in atherosclerosis. Based on the clinical studies and immunological findings, it seems that the differences in the specificity of antiphospholipid antibodies may reflect to their pathogenetic mechanisms and, finally, to their clinical consequences. The present review suggests that antibodies to oxidized LDL may not interfere directly with blood coagulation, but seem to have importance in the inflammation of the vessel wall in atherosclerosis and in vasculitis. Instead, antibodies to beta 2-glycoprotein I and to prothrombin show a closer association with thrombosis. It is possible that in the atherosclerotic plaque, the plasma proteins, such as beta 2-glycoprotein I or prothrombin, are bound to the endothelial surface and antibodies to cryptic epitopes revealed in these proteins are induced. These antibodies may contribute to the formation of atherosclerotic thrombosis by changing the balance of haemostasis toward hypercoagulative state.

Antibodies, Antiphospholipid↗
PubMed1997

Native and multimeric vitronectin exhibit similar affinity for heparin. Differences in heparin binding properties induced upon denaturation are due to self-association into a multivalent form.

For many years, the concept that the heparin-binding sequence is sequestered within vitronectin and exposed upon denaturation of the protein has guided experimental design and interpretation of related structure-function studies on the protein. To evaluate binding of heparin to both native and denatured/renatured vitronectin, methods for monitoring binding in solution have been developed. A fluorescence method based on changes in an extrinsic probe attached to heparin has been used to evaluate heparin binding to native and denatured/renatured vitronectin. This approach indicates that there are not major differences in intrinsic heparin-binding affinities between native and renatured protein and invalidate the currently accepted model for a cryptic heparin-binding sequence in the protein. Denaturation and renaturation of vitronectin under near physiological solution conditions is accompanied invariably by self-association of the protein into a multimeric form (Zhuang, P., Blackburn, M. N., and Peterson, C. B. (1996) J. Biol. Chem. 271, 14323-14332), resulting in exposure of multiple heparin-binding sites on the surface of the oligomer. On the basis of the binding data from solution studies and interaction of the native monomer and the denatured multimeric form of vitronectin with a heparin column, along with evaluation of the ionic strength dependence of heparin binding to these vitronectin forms in solution, an alternative model is favored to account for the altered heparin binding properties of vitronectin associated with denaturation of the protein. This model proposes that multivalent interactions between heparin and multimeric vitronectin are responsible for differences in heparin affinity chromatography and ionic strength dependence compared with the native protein.

Animals↗
PubMed1997

Sequence analysis of the small cryptic Xanthomonas campestris pv. vesicatoria plasmid pXV64 encoding a Rep protein similar to gene II protein of phage 12-2.

The complete nucleotide sequence (1,851 bp) was determined for the Xanthomonas campestris pv. vesicatoria plasmid pXV64. Sequence analysis revealed an intergenic region (IG) of 355 bp and two oppositely running open reading frames, ORF1 and ORF2, encoding polypeptides of 39 and 16 kDa, respectively. While the function of ORF2 is not known, ORF1 is suggested to be the gene encoding Rep protein based on (i) similarity in amino acid sequence to that of the gene II protein (gIIP) of filamentous phage 12-2, (ii) presence of a sequence in the ori-containing region which is similar to the sequence around the Rep nicking site in some rolling circle-replicating replicons, and (iii) ability to support replication in trans of the region containing pXV64 ori (392 bp) which is located within the region including IG and a short stretch in the N-terminus of ORF2.

Amino Acid Sequence↗
PubMed1989

Activation of HIV-enhancer binding activity by mild detergents in human T cells.

Binding activity to the HIV enhancer, a sequence highly homologous to the NF-KB enhancer, is inducible by PMA in human Jurkat T cells. We here show that, similar to what is observed for NF-KB in B cells, mild detergents, such as Deoxycholate, reveal a cryptic binding activity in protein extracts from non activated cells. The complex revealed by detergent treatment correspond to the PMA inducible, highly sequence specific species. This result suggest the existence of an inhibitor in non activated cells, which is released by the detergent, as has been demonstrated in B cells. Mild detergent treatment of PMA activated extracts resulted in superinduction of the specific complex. These results suggest that regulation of HIV enhancer binding protein is similar to regulation of NF-KB in B cells.

Base Sequence↗
PubMed2003

Hemostatic regulators of tumor angiogenesis: a source of antiangiogenic agents for cancer treatment?

The maintenance of vascular integrity and control of blood loss are regulated by a sophisticated system of circulating and cell-associated hemostatic factors. These factors control local platelet aggregation, the conversion of soluble fibrinogen to an insoluble fibrin polymer, and the dissolution of fibrin. However, hemostatic factors are also involved in a number of physiologic processes, including development, tissue remodeling, wound repair, reproduction, inflammation, and angiogenesis. In this review, we outline ways in which angiogenesis is coordinated with and regulated by hemostasis. We focus on inhibitors of angiogenesis contained within platelets or harbored as cryptic fragments of hemostatic proteins and assess the experimental and preclinical evidence for their ability to inhibit tumor angiogenesis and, thus, their potential to be anticancer agents. Finally, we review the results of recent clinical trials involving angiogenesis inhibitors and the evidence that antiangiogenic therapy may be associated with hemostatic complications.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Angiogenesis inhibitors found within the haemostasis pathway.

Angiogenesis, the development of new blood vessels from the existing vasculature, and haemostasis, the coagulation cascade leading to formation of a clot, are among the most consistent host responses associated with cancer. Importantly, these two pathways interrelate, with blood coagulation and fibrinolysis influencing tumor angiogenesis directly, thereby contributing to tumor growth. Moreover, many endogenous inhibitors of angiogenesis are found within platelets or harboured as cryptic fragments of haemostatic proteins. In this review we outline ways in which angiogenesis is coordinated and regulated by haemostasis in human cancer. Then we detail the experimental and pre-clinical evidence for the ability of many of these endogenous proteins to inhibit tumor angiogenesis and thus their potential to be anti-cancer agents, with particular reference to any clinical trials.

Angiogenesis Inhibitors↗
PubMed2005

Cripto monoclonal antibodies.

The success of molecular target-based cancer therapy exampled by Herceptin targeting Her2 indicates that cancer immunotherapy involves identifying and targeting key molecular drivers of cancer. Recently, the human Cripto, a founding member of the epidermal growth factor-Cripto-FRL1-Cryptic (EGF-CFC) protein family has been demonstrated to be a unique molecule and could be targeted by anti-Cripto monoclonal antibodies for the treatment of cancer. Cripto plays an important role in embryonic development, tumorigenesis, cancer cell proliferation and survival. Cripto is upregulated in most epithelial cancers but is absent or weakly expressed in normal cells. Cripto expression is associated with tumorigenesis and invasion. Cripto is also involved in tumor metastasis, which is strongly supported by the recent discovery that the phenotypic changes of increased motility and invasiveness of cancer cells are reminiscent of the epithelial mesenchymal transition (EMT) that occurs during embryonic development. In this review, we emphasize that the EGF-like region of Cripto plays a critical role in Cripto signaling-mediated tumor growth and EMT. Therefore the EGF-like region should be regarded as a therapeutic point for monoclonal antibody (MAb) intervention. The mechanisms of action of these MAbs to the EGF-like region of Cripto are most likely through intervention of c-Src signaling. The CFC region of Cripto is another region to be targeted for treatment of cancer, as the Cripto can bind to activin B through the CFC region to stimulate cell proliferation. The MAbs to the CFC region block the binding of Cripto and activin B and result in an inhibition of cell growth. Therefore the MAbs to Cripto may be of value in the treatment of various cancers.

Animals↗
PubMed2005

Cripto as a target for cancer immunotherapy.

One of the recent, significant advances in cancer immunotherapy is the identification of molecules as targets which regulate cell growth by induction of proliferation and survival signalling pathways. Among them, epidermal growth factor receptor and Her2 have been effectively targeted by monoclonal antibodies. Currently, the treatment of cancer has limitations and most cancer deaths result from the local invasion and distant metastasis of tumour cells. An important insight for the understanding of tumour invasion and metastasis came from the recent discovery that the phenotypic changes of increased motility and invasiveness of cancer cells are reminiscent of the epithelial-mesenchymal transition (EMT) that occurs during embryonic development. The human Cripto, a member of the epidermal growth factor-Cripto, Frl1, and Cryptic (EGF-CFC) protein family and a signalling protein during early embryonic development, plays an important role in cancers. Cripto is attached to the cell membrane through a glycosyl-phosphatidylinositol motif, and is upregulated in a wide range of epithelial cancers. In this paper the authors review the role of Cripto expression in tumourigenesis and in EMT to promote tumour invasion, with emphasis that the unique EGF-like region of Cripto plays a critical role in Cripto signalling-mediated tumour growth and EMT. Therefore, the region should be regarded as a therapeutic point for interruption of the oncogenic and metastatic potential of Cripto for cancer immunotherapy.

Amino Acid Sequence↗
PubMed1999

Cryptic epitopes on alpha-fetoprotein induce spontaneous immune responses in hepatocellular carcinoma, liver cirrhosis, and chronic hepatitis patients.

To determine alpha-fetoprotein (AFP) immunogenicity in vivo, the presence of antibodies in sera of 60 hepatocellular carcinoma, 15 liver cirrhosis, and 15 chronic hepatitis patients was evaluated by Western blotting and immunoprecipitation analyses using purified human AFP. High titers of anti-AFP immunoglobulins were detected in 14 hepatocellular carcinomas (P = 0.0006), 3 liver cirrhosis (P = 0.0173), and 1 chronic hepatitis patient, but they were not detected in 40 healthy individuals. Therefore, spontaneous immune responses to AFP are significantly associated to liver diseases (P = 0.0015). Patient immunoglobulins recognized proteic linear epitopes that were cryptic in the native protein, as demonstrated by their restricted reactivity with denatured deglycosylated AFP. Thus, in pathological liver conditions, tolerance to this self-molecule is circumvented. The identification of AFP immunogenic epitopes may contribute to defining novel immunotherapeutic strategies targeting this antigen.

Adult↗
PubMedDate not supplied

[Hutchinson-Gilford progeria in the light of contemporary genetics].

Hutchinson-Gilford progeria causing premature aging of children is a genetic disease and according to most authors has an autosomal dominant inheritance. It has been regarded as a model of the process of aging. In 2003 mutations in the LMNA gene, localized f in chromosome 1, responsible for the disease, were identified. The most frequent mutation is located in exon 11, C1824T and does not change glycin in position 608 of protein chain, but activates cryptic splice site. This results in shortened lamin A synthesis which is named progerin. Point mutations in other exons of LMNA, found in progeria patients, are responsible for atypical phenotypes.

Aging↗