Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Origin Recognition Complex”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,261 records · Page 70Linked to original sources
PubMed1995

Numerical syndromology: a mathematical approach to the nosology of complex phenotypes.

Numerical taxonomy is defined by Sneath and Sokal as the grouping of taxonomic units on the basis of their character states by numerical methods of multivariate data analysis, and syndromology as the study of multiple congenital anomaly (MCA) syndromes and of their nosology. We present here an application of those methods to the analysis of overlapping syndromes. The main advantage of numerical taxonomy is that it allows simultaneous objective and unweighted analysis of multiple traits, giving the possibility to test mathematically the clinical hypotheses about the heterogeneity between closely resembling syndromes and uncovering objective patterns of anomalies, to be compared with the subjective pattern recognition process which characterizes most of the diagnostic approach in syndromology. In this paper, we explored 5 syndromes whose most severe expression belongs to the cerebroacrovisceral early lethality (CAVE) phenotype: hydrolethalus, severe Smith-Lemli-Opitz, orofaciodigital type VI (Varadi-Papp), holoprosencephaly-polydactyly, and Pallister-Hall syndromes. Fifty-five published cases, including many overlapping cases, were submitted to principal factor analysis followed by hierarchical clustering and graphical scaling. Results show that the 5 syndromes clearly constitute independent phenotypic entities, that some of the original diagnoses have to be reconsidered, and that many of the overlapping cases may be unambiguously set in one category. Hypothalamic hamartoblastoma appears to be a nonspecific dysplasia occurring in any of the 5 disorders.

Abnormalities, Multiple↗
PubMed2006

Investigating the basis of substrate recognition in the pC221 relaxosome.

The nicking of the origin of transfer (oriT) is an essential initial step in the conjugative mobilization of plasmid DNA. In the case of staphylococcal plasmid pC221, nicking by the plasmid-specific MobA relaxase is facilitated by the DNA-binding accessory protein MobC; however, the role of MobC in this process is currently unknown. In this study, the site of MobC binding was determined by DNase I footprinting. MobC interacts with oriT DNA at two directly repeated 9 bp sequences, mcb1 and mcb2, upstream of the oriT nic site, and additionally at a third, degenerate repeat within the mobC gene, mcb3. The binding activity of the conserved sequences was confirmed indirectly by competitive electrophoretic mobility shift assays and directly by Surface Plasmon Resonance studies. Mutation at mcb2 abolished detectable nicking activity, suggesting that binding of this site by MobC is a prerequisite for nicking by MobA. Sequential site-directed mutagenesis of each binding site in pC221 has demonstrated that all three are required for mobilization. The MobA relaxase, while unable to bind to oriT DNA alone, was found to associate with a MobC-oriT complex and alter the MobC binding profile in a region between mcb2 and the nic site. Mutagenesis of oriT in this region defines a 7 bp sequence, sra, which was essential for nicking by MobA. Exchange of four divergent bases between the sra of pC221 and the related plasmid pC223 was sufficient to swap their substrate identity in a MobA-specific nicking assay. Based on these observations we propose a model of layered specificity in the assembly of pC221-family relaxosomes, whereby a common MobC:mcb complex presents the oriT substrate, which is then nicked only by the cognate MobA.

Bacterial Proteins↗
PubMedDate not supplied

Arterial thromboembolism of the upper extremity associated with the thoracic outlet syndrome.

Acute arterial thromboembolism of the upper extremity associated with the thoracic outlet syndrome is much less frequent than the neurologic manifestations, but is a potential threat to the viability of the limb if not recognized in time. The thromboembolic process originates in a damaged subclavian artery as a result of its prolonged compression, usually by congenital, much more rarely, by acquired anomalies of anatomical structures at the thoracic outlet. Major embolic complications usually occur after months or years of episodal and repetitive microemboli. A comprehensive arteriographic evaluation of the entire arterial tree in addition to other tests is essential for diagnosis. Four patterns of arterial findings are described. The scope of the surgical treatment of these manifestations it twofold: (1) decompression of the subclavian artery and (2) repair of the arterial lesions, often with additional thoracic sympathectomy. Results of management of the arterial lesions are described in three groups, based mostly on a review of data from the literature. In recent years a more aggressive approach to these lesions appears to have resulted in better management of this complex entity. A case report will illustrate some the clinical and pathological aspects of this problem. Early recognition of this unusual thromboembolic process is necessary for achieving a more complete limb salvage.

Arm↗
PubMed2005

Role of receptor-mediated endocytosis in the formation of vaccinia virus extracellular enveloped particles.

Infectious intracellular mature vaccinia virus particles are wrapped by cisternae, which may arise from trans-Golgi or early endosomal membranes, and are transported along microtubules to the plasma membrane where exocytosis occurs. We used EH21, a dominant-negative form of Eps15 that is an essential component of clathrin-coated pits, to investigate the extent and importance of endocytosis of viral envelope proteins from the cell surface. Several recombinant vaccinia viruses that inducibly or constitutively express an enhanced green fluorescent protein (GFP)-EH21 fusion protein were constructed. Expression of GFP-EH21 blocked uptake of transferrin, a marker for clathrin-mediated endocytosis, as well as association of adaptor protein-2 with clathrin-coated pits. When GFP-EH21 was expressed, there were increased amounts of viral envelope proteins, including A33, A36, B5, and F13, in the plasma membrane, and their internalization was inhibited. Wrapping of virions appeared to be qualitatively unaffected as judged by electron microscopy, a finding consistent with a primary trans-Golgi origin of the cisternae. However, GFP-EH21 expression caused a 50% reduction in released enveloped virions, decreased formation of satellite plaques, and delayed virus spread, indicating an important role for receptor-mediated endocytosis. Due to dynamic interconnection between endocytic and exocytic pathways, viral proteins recovered from the plasma membrane could be used by trans-Golgi or endosomal cisternae to form new viral envelopes. Adherence of enveloped virions to unrecycled viral proteins on the cell surface may also contribute to decreased virus release in the presence of GFP-EH21. In addition to a salvage function, the retrieval of viral proteins from the cell surface may reduce immune recognition.

Adaptor Protein Complex 2↗
PubMed1994

Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness.

Recognition by T-cell antigen receptors (TCRs) of processed peptides bound to major histocompatibility complex (MHC) molecules is required for the initiation of most T-lymphocyte responses. Despite the availability of soluble forms of TCRs and MHC heterodimers, this interaction has proven difficult to study directly due to the very low affinity. We report here on the kinetics of TCR binding to peptide/MHC complexes in a cell-free system using surface plasmon resonance. The apparent association rates for the interactions of related peptide/MHC complexes to one such TCR are relatively slow (900-3000 M-1.s-1) and dissociation rates are very fast (0.3-0.06 s-1) with t1/2 of 2-12 s at 25 degrees C. The calculated affinity of the engineered soluble molecules compares well with previously reported competition data for native TCRs or competition data reported here for native peptide/MHC complexes, indicating that these soluble heterodimers bind in the same manner as the original molecules expressed on cells. We also find that the peptide variants which give weaker T-cell stimulatory responses have similar affinities but distinctly faster dissociation rates compared with the original peptide (when loaded onto the MHC molecule) and that this later property may be responsible for their lower activity. This has implications for both downstream signaling events and models of TCR-peptide antagonists.

Amino Acid Sequence↗
PubMed1981

MIs locus recognition by a cloned line of H-2-restricted influenza virus-specific cytotoxic T lymphocytes.

This report demonstrates the expression of strong MIs locus MIsd) recognition by a cloned line of H-2-restricted influenza virus-specific CTL. This clone of F1 (H-2b/d; MIsb) origin was found to specifically proliferate in response to uninfected cells of CBA/J (H-2k, MIsd) origin but not to uninfected B10.BR or CBA/CaJ cells (H-2k, MIsb). In addition, proliferation by this cTL line was observed in response to histocompatible cells expressing cross-reactive MIsa determinants (DBA/2, NZB; H-2d, MIsa). This recognition was observed only at the level of CTL proliferation. The CTL line exhibited no cytotoxic activity for target cells of these MIs types. These observations are contrasted with the response of another cloned H-2-restricted influenza-specific CTL line that simultaneously exhibits alloreactivity for H-2k. The significance of these results for T lymphocyte recognition is discussed.

Animals↗
PubMed2001

Antiparasitic properties of medicinal plants and other naturally occurring products.

Parasitic diseases remain a major public health problem affecting hundreds of millions of people, particularly in tropical developing countries. The limited availability and affordability of pharmaceutical medicines means that the majority of the world's population depends on traditional medical remedies, and it is estimated that some 20,000 species of higher plant are used medicinally throughout the world. Many well-known drugs listed in the modern pharmacopoeia have their origins in nature, including, for example, quinine from the bark of the Cinchona tree for the treatment of malaria, which has been followed by the subsequent development of the synthetic derivatives chloroquine, amodiaquine, primaquine and mefloquine. More recently, the wider recognition of the antimalarial activity of artemisinin from the herb Artemisia annua has led current research to focus on the development of a large number of synthetic and semisynthetic compounds, which are more active than artemisinin. There is an increasing awareness of the potential of natural products, which may lead to the development of much-needed new antiparasitic drugs. In this chapter, we have drawn together a comprehensive list of medicinal plants and other natural products that have been shown to have activity against human and, to a lesser extent, animal parasites. In addition, some of the opportunities and difficulties in working with natural products have been reviewed and discussed, including the problems involved with evaluating complex mixtures of compounds which may occur in extracts, problems associated with differentiating between general cytotoxicity and genuine antiparasitic activity, and the hope that new technologies will rapidly accelerate new drug discovery and development in this field. Nevertheless, the way forward for natural product medicines, including the conservation of recognized natural products and protection of general biodiversity, the discovery and development process, and the promotion and usage of existing remedies, presents some difficult challenges. Following an initiative by the World Health Organization in August 2000, there is now the opportunity to evaluate scientifically many more traditional medicines and other natural products in validated antiparasite and toxicity screens, which will help establish which substances have potential for new pharmaceutical products. The use of 'untested' traditional medicines will no doubt continue, and there is an urgent need to distinguish between the efficacious and safe products and the ineffective and/or unsafe products, particularly since many remedies are being more widely promoted in developing countries.

Animals↗
PubMed2005

Delineating fluid-filled region boundaries in optical coherence tomography images of the retina.

We evaluate the ability of a deformable model to yield accurate shape descriptions of fluid-filled regions associated with age-related macular degeneration. Calculation of retinal thickness and volume by the current optical coherence tomography (OCT) system includes fluid-filled regions or lesions along with actual retinal tissue. In order to quantify these lesions independently from the retinal tissue, they must be outlined. A deformable model was applied to OCT images of retinas demonstrating cystoids and subretinal fluid spaces. Several implementation issues were addressed in order to choose appropriate parameters. The use of a nonlinear anisotropic diffusion filter to suppress speckle noise while at the same time preserving the edges of the original image was explored. Once the contours of the lesions were outlined, quantitative analysis of the surface area and volume of the lesions was performed. The deformable model could accurately outline fluid-filled regions within the retina. The detection method tested proved effective in capturing the complexity of fluid-filled regions in OCT images. Deformable models combined with nonlinear anisotropic diffusion filtering show promise in the detection of retinal features of interest for diagnosis in clinical OCT images. Thus, fluid-filled region detection may significantly aid in analysis of treatments and diagnosis.

Algorithms↗
PubMed2006

Gene selection algorithms for microarray data based on least squares support vector machine.

BACKGROUND: In discriminant analysis of microarray data, usually a small number of samples are expressed by a large number of genes. It is not only difficult but also unnecessary to conduct the discriminant analysis with all the genes. Hence, gene selection is usually performed to select important genes. RESULTS: A gene selection method searches for an optimal or near optimal subset of genes with respect to a given evaluation criterion. In this paper, we propose a new evaluation criterion, named the leave-one-out calculation (LOOC, A list of abbreviations appears just above the list of references) measure. A gene selection method, named leave-one-out calculation sequential forward selection (LOOCSFS) algorithm, is then presented by combining the LOOC measure with the sequential forward selection scheme. Further, a novel gene selection algorithm, the gradient-based leave-one-out gene selection (GLGS) algorithm, is also proposed. Both of the gene selection algorithms originate from an efficient and exact calculation of the leave-one-out cross-validation error of the least squares support vector machine (LS-SVM). The proposed approaches are applied to two microarray datasets and compared to other well-known gene selection methods using codes available from the second author. CONCLUSION: The proposed gene selection approaches can provide gene subsets leading to more accurate classification results, while their computational complexity is comparable to the existing methods. The GLGS algorithm can also better scale to datasets with a very large number of genes.

Algorithms↗
PubMed2001

The cadherin superfamily: diversity in form and function.

Over recent years cadherins have emerged as a growing superfamily of molecules, and a complex picture of their structure and their biological functions is becoming apparent. Variation in their extracellular region leads to the large potential for recognition properties of this superfamily. This is demonstrated strikingly by the recently discovered FYN-binding CNR-protocadherins; these exhibit alternative expression of the extracellular portion, which could lead to distinct cell recognition in different neuronal populations, whereas their cytoplasmic part, and therefore intracellular interactions, is constant. Diversity in the cytoplasmic moiety of the cadherins imparts specificity to their interactions with cytoplasmic components; for example, classical cadherins interact with catenins and the actin filament network, desmosomal cadherins interact with catenins and the intermediate filament system and CNR-cadherins interact with the SRC-family kinase FYN. Recent evidence suggests that CNR-cadherins, 7TM-cadherins and T-cadherin, which is tethered to the membrane by a GPI anchor, all localise to lipid rafts, specialised cell membrane domains rich in signalling molecules. Originally thought of as cell adhesion molecules, cadherin superfamily molecules are now known to be involved in many biological processes, such as cell recognition, cell signalling, cell communication, morphogenesis, angiogenesis and possibly even neurotransmission.

Animals↗
PubMed1991

The image of the "brain surgeon" in American culture: the influence of Harvey Cushing.

In contemporary American culture, the term "brain surgeon" conjures up the image of an intensely single-minded professional, who deals with terribly complex matters of life and death. These descriptors find their personification in Harvey Cushing, because they are derived directly from him. This hypothesis was tested by a complete search of the New York Times Index and the Reader's Guide to Periodical Literature for the years 1919 to 1942. All entries for Harvey Cushing were reviewed in the original sources. In the New York Times, Cushing's first significant exposure was in response to his winning a Pulitzer Prize in 1925. Major editorial coverage began in 1934, and was especially prominent with the publication of From a Surgeon's Journal in 1936. The process of lionizing Cushing by creating an overdrawn caricature reached its apotheosis in Time magazine in 1939. The Time article was actually a report of Cushing's 70th birthday party. It expounded all of the descriptors that are now associated with "brain surgeon". Thus, it was Cushing's literary skills that initially brought him recognition from editors who were arbiters of public opinion. This attention seems to have been the conduit to his mythologization by the larger public. Although unnamed, it is really Cushing's image that still persists as the prototypical "brain surgeon" in the collective American consciousness.

History, 20th Century↗
PubMed2000

The alloreactive and self-restricted CD4+ T cell response directed against a single MHC class II/peptide combination.

The cellular basis for allograft rejection derives from the strong T cell response to cells bearing foreign MHC. While it was originally assumed that alloreactive T cells focus their recognition on the polymorphic residues that differ between syngeneic and allogeneic MHC molecules, studies with MHC class I-restricted CTL have shown that MHC-bound peptides play a critical role in allorecognition. It has been suggested that alloreactive T cells depend more strongly on interactions with the MHC molecule than with the associated peptide, but there is little evidence to support this idea. Here we have studied the alloreactive and self-restricted response directed against the class II H2-Ab molecule bound with a single peptide, Ep, derived from the H2-Ealpha chain. This MHC class II-peptide combination was a poor target and stimulator of alloreactive CD4+ T cell responses, indicating that MHC-bound peptides are as important for alloreactive CD4+ T cells as they are for alloreactive CTL. We also generated alloreactive T cells with exquisite specificity for the Ab/Ep complex, and compared their reactivity with self-restricted T cells specific for the same Ab/Ep complex. Our results showed that peptide-specific alloreactive T cells, as compared with self-restricted T cells, were more sensitive to peptide stimulation, but equally sensitive to amino acid substitutions in the peptide. These findings indicate that alloreactive and self-restricted T cells interact similarly with their MHC/peptide ligand.

Amino Acid Sequence↗
PubMed1996

Organization of connections between the amygdaloid complex and the perirhinal and parahippocampal cortices in macaque monkeys.

Neuroanatomical studies in macaque monkeys have demonstrated that the perirhinal and parahippocampal (PRPH) cortices are strongly interconnected with the hippocampal formation. Recent behavioral evidence indicates that these cortical regions are importantly involved in normal recognition memory function. The PRPH cortices are also interconnected with the amygdaloid complex, although comparatively little is known about the precise topography of these connections. We investigated the topographic organization of reciprocal connections between the amygdala and the PRPH cortices by placing anterograde and retrograde tracers throughout these three regions. We found that there was an organized arrangement of connections between the amygdala and the PRPH cortices and that the deep (lateral, basal, and accessory basal) nuclei of the amygdaloid complex were the source of most connections between the amygdala and the PRPH cortices. The temporal polar regions of the perirhinal cortex had the strongest and most widespread interconnections with the amygdala. Connections from more caudal levels of the perirhinal cortex had a more discrete pattern of termination. Perirhinal inputs to the amygdala terminated primarily in the lateral nucleus, the magnocellular and parvicellular divisions of the basal nucleus, and the magnocellular division of the accessory basal nucleus. Return projections originated predominately in the lateral nucleus, the intermediate and parvicellular divisions of the basal nucleus, and the magnocellular division of the accessory basal nucleus. The interconnections between the amygdala and the parahippocampal cortex were substantially less robust than those with the perirhinal cortex and mainly involved the basal nucleus. Area TF was more strongly interconnected with the amygdala than was area TH. Input from the parahippocampal cortex terminated predominantly in the lateral half of the parvicellular division of the basal nucleus but also to a lesser extent in the magnocellular division of the basal nucleus and the lateral nucleus. Return projections originated predominantly in the magnocellular division of the basal nucleus and were directed almost exclusively to area TF.

Amygdala↗
PubMed1994

Prenatal echocardiographic diagnosis of right atrial isomerism.

A prenatal diagnosis of right atrial isomerism is often inferred through the recognition of a constellation of cardiac anomalies on the four-chamber view or by the detection of visceral heterotaxy and asplenia. However, the actual occurrence of discordance between the arrangement of the atria and thoracic and abdominal organs makes the identification of the morphology of both atrial appendages the only reliable way to make a final diagnosis of atrial isomerism. Three cases of right atrial isomerism with visceral heterotaxy and a complex cardiac defect, diagnosed in utero by cross-sectional and colour flow Doppler echocardiography, are reported. In all the patients, the right atrial isomerism was associated with an atrioventricular septal defect, a single aortic outlet from the right ventricle, and total anomalous venous return. The diagnosis of right atrial isomerism, always confirmed by neonatal re-evaluation and/or by post-mortem examination, was made through identifying two pyramidal atrial appendages in an echocardiographic transverse plane at the level of the atria and of the origin of the great arteries. This report demonstrates that a final intrauterine diagnosis of atrial isomerism is possible, whatever the visceral situs is.

Echocardiography, Doppler↗
PubMed1985

Discrimination and recognition of tonal melodies after unilateral cerebral excisions.

Groups of surgical patients with unilateral temporal- or frontal-lobe lesions and normal control subjects were tested in melodic discrimination and recognition tasks. The discrimination task required detection of a single-note change in a pair of short unfamiliar tonal melodies. The altered note either violated or preserved the contour, the scale, or both, of the original melody. Recognition required that the melodies used in the discrimination task be recognized from among a set of similar foils. Right temporal-lobe patients performed most poorly in discrimination. Further analysis showed that excision of the primary auditory receiving area. Heschl's gyri from either side resulted in a deficit which was independent from, but additive with, the deficit caused by right temporal lobectomy. In the recognition task, both temporal-lobe groups were impaired as compared to control. The use of scale and contour cues was similar for all groups, indicating that the deficits observed are not attributable to failure to process one of these cues. Right frontal-lobe lesioned patients differed from the others in response bias, but performed as well as controls on both tasks. The results are interpreted as evidence for two processes in melodic discrimination, one due to short-term memory mechanisms, the other attributable to a deficit in processing complex auditory patterns.

Adult↗
PubMed1994

Comparison of cell lines deficient in antigen presentation reveals a functional role for TAP-1 alone in antigen processing.

Cytotoxic T lymphocytes (CTL) recognize antigenic peptides bound to major histocompatibility complex class I antigens on the cell surface of virus-infected cells. It is believed that the majority of peptides originate from cytoplasmic degradation of proteins assumed to be mediated by the "20S" proteasome. Cytosolic peptides are then translocated, presumably by transporters associated with antigen processing (TAP-1 and -2), into the lumen of the endoplasmic reticulum (ER) where binding and formation of the ternary complex between heavy chain, beta2-microglobulin (beta 2m) and peptide occurs. In this study, we have analyzed and compared the phenotype of two mutant cell lines, the thymoma cell line RMA-S and a small lung carcinoma cell line CMT.64, in order to address the mechanism that underlies the antigen processing deficiency of CMT.64 cells. Unlike RMA-S cells, vesicular stomatitis virus (VSV)-infected CMT.64 cells are not recognized by specific CTL. Interferon gamma (IFN-gamma) treatment of CMT.64 cells restores the ability of these cells to process and present VSV in the context of Kb. We show that although CMT.64 cells express a low level of beta 2m, the recognition of VSV-specific CTL is not restored by increasing the amount of beta 2m synthesized in CMT.64 cells. In addition, we find that CMT.64 cells express moderate levels of Kb heavy chain molecules, but most of it is unstable and rapidly degraded in the absence of IFN-gamma treatment. We infer that the antigen processing deficiency does not lie at the level of beta 2m or Kb production. We find also that the mRNAs for both TAP-1 and -2 are present in RMA and RMA-S cells but are absent in uninduced CMT.64 cells. Upon IFN-gamma induction, both mRNAs are highly expressed in CMT-64 cells. In addition, we find that the low molecular mass polypeptides 2 and 7, and additional components of the proteasome are induced by IFN-gamma in CMT-64 cells. Finally, introduction of the rat TAP-1 gene in CMT.64 cells restores CTL recognition of VSV-infected cells. These results indicate that a TAP-1 homodimer may translocate peptides in the ER and explain partially the CMT.64 defect and the RMA-S phenotype. These findings link a dysfunction in the transport and/or generation of antigenic peptides to the capacity of tumor cells to evade immunosurveillance and provide a unique model system to dissect this phenomenon.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Speech- and sound-segmentation in dyslexia: evidence for a multiple-level cortical impairment.

Developmental dyslexia involves deficits in the visual and auditory domains, but is primarily characterized by an inability to translate the written linguistic code to the sound structure. Recent research has shown that auditory dysfunctions in dyslexia might originate from impairments in early pre-attentive processes, which affect behavioral discrimination. Previous studies have shown that whereas dyslexic individuals are deficient in discriminating sound distinctions involving consonants or simple pitch changes, discrimination of other sound aspects, such as tone duration, is intact. We hypothesized that such contrasts that can be discriminated by dyslexic individuals when heard in isolation are difficult to identify when occurring within words or structurally similar complex sound patterns. In the current study, we addressed how segments of pseudo-words and their non-speech counterparts are processed in dyslexia. We assessed the detection of long-duration differences in segments of these stimuli and identified the brain processes that could be associated with the behavioral results. Consistent with previous studies, we found no early cortical sound-duration discrimination deficit in dyslexia. However, differences between impaired and non-impaired readers were found in the brain processes associated with sound-change recognition as well as in the behavioral performance. This suggests that even when the early, automatic, sound discrimination processes are intact in dyslexic individuals, deficits in the later, attention-dependent processes may lead to impaired perception of speech and other complex sounds.

Acoustic Stimulation↗
PubMed2025

The Use of APC/C Antagonists to Promote Mitotic Catastrophe in Cancer Cells.

The multiprotein subunit E3 ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C) plays a key role in the control of mitosis progression. APC/C is the ultimate effector of the Spindle Assembly Checkpoint (SAC), the signaling system of higher organisms including the human that monitors the proper attachment of chromosomes to microtubules during cell division. Defects in this process result in genome instability, aneuploidy, premature aging, and cancer. APC/C roles in the SAC require its activation by the protein Cdc20. Interfering with APC/C activation by Cdc20 impairs APC/C substrate recognition, resulting in a delayed mitotic exit and eventually inducing cell death. This may be advantageous for the treatment of cancer and malignancies associated with SAC dysregulation. Here we describe a protocol to interfere with mitotic exit through the use of commercially available (Apcin, proTAME) as well as innovative small molecules we have developed that function as antagonists of APC/C activation by Cdc20. We show that the use of these molecules alone and in combination is effective to promote mitotic catastrophe and suppress cell expansion in 2D and 3D (spheroids) cancer cells of different tissue origin, including breast, cervical, and ovarian cancer.

Humans↗