• K cell mediated haemolysis: influence of large numbers of unsensitized cells on the antibody-dependent lysis of anti-D-sensitized erythrocytes by human lymphocytes.

      Bakács, T; Kimber, Ian; Ringwald, G; Moore, Michael; Department of Immunology, Paterson Laboratories, Christie Hospital and Holt Radium Institute, Wilmslow Road, Withington, Manchester M20 9BX, UK (1984-07)
      The inhibition of K cell mediated haemolysis of anti-D-sensitized human red blood cells by unsensitized erythrocytes has been demonstrated. Inhibition of lysis was non-competitive in nature and influenced by the size and number of unsensitized cells. However, even in the presence of high inhibitor: target cell ratios (50:1) haemolysis, although reduced, was still effected suggesting that K cells are highly motile and capable of recognizing and destroying minority populations of antibody-sensitized erythrocytes. These data are compatible with a role for cytotoxic lymphocytes in the intravascular lysis of autoantibody or alloantibody-sensitized red cells.
    • K-ras gene mutation in colorectal adenomas and carcinomas from familial adenomatous polyposis patients.

      Boughdady, I S; Kinsella, Anne R; Haboubi, N Y; Schofield, Philip F; Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK. (1992-08)
      Colorectal adenomas and carcinomas from familial adenomatous polyposis (FAP) patients were screened for the presence of K-ras gene mutations at codon 12 using an in vitro amplification step (polymerase chain reaction) followed by dot blot analysis using oligonucleotide probes specific for different mutations at codon 12. We examined 28 colorectal adenomas and two colorectal carcinomas from 12 FAP patients and observed a mutation at codon 12 in seven adenomas and in both carcinomas. The frequency of K-ras gene mutations in colorectal tumours from FAP patients is similar to those in cases of sporadic adenomas and sporadic colorectal carcinomas indicating that the mechanisms involved in their development may be similar.
    • K-ras gene mutations in adenomas and carcinomas of the colon.

      Boughdady, I S; Kinsella, Anne R; Haboubi, N Y; Schofield, Philip F; Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK. (1992-08)
      DNA extracted from 29 colorectal carcinomas and 40 sporadic adenomas was amplified by the polymerase chain reaction (PCR) and analysed for the presence of K-ras gene mutations at codon 12 using a panel of synthetic oligonucleotide probes specific for normal and mutated sequences. The presence of mutations was correlated with various histopathological and clinical data. Ten carcinomas (34.5%) and 14 sporadic adenomas (35%) showed K-ras mutations at codon 12. In the carcinoma group, no apparent correlation was found between the presence of mutant oncogenes and the degree of histological differentiation, Dukes' staging or the development of distant metastasis. In the adenoma group, the frequency of mutations increased with the size of the adenoma and the severity of the dysplastic changes. This study confirms that ras gene mutations are common and early events in colon carcinogenesis. They appear to give a selective growth advantage to those polyps with mutations which leads to their increase in size and thus possibly prepare the ground for malignant transformation.
    • The karyotype of Alligator mississippiensis, and chromosomal mapping of the ZFY/X homologue, Zfc.

      Valleley, E M; Harrison, Christine J; Cook, Yvonne; Ferguson, M W; Sharpe, P T; School of Biological Sciences, University of Manchester, UK. (1994-12)
      Comparative mapping studies of X-linked genes in mammals have provided insights into the evolution of the X chromosome. Many reptiles including the American alligator, Alligator mississippiensis, do not appear to possess heteromorphic sex chromosomes, and sex is determined by the incubation temperature of the egg during embryonic development. Mapping of homologues of mammalian X-linked genes in reptiles could lead to a greater understanding of the evolution of vertebrate sex chromosomes. One of the genes used in the mammalian mapping studies was ZFX, an X-linked copy of the human ZFY gene which was originally isolated as a candidate for the mammalian testis-determining factor (TDF). ZFX is X-linked in eutherians, but maps to two autosomal locations in marsupials and monotremes, close to other genes associated with the eutherian X. The alligator homologue of the ZFY/ZFX genes, Zfc, has been isolated and described previously. A detailed karyotype of A. mississippiensis is presented, together with chromosomal in situ hybridisation data localising the Zfc gene to chromosome 3. Further chromosomal mapping studies using eutherian X-linked genes may reveal conserved chromosomal regions in the alligator that have become part of the eutherian X chromosome during evolution.
    • KDM1 histone lysine demethylases as targets for treatments of oncological and neurodegenerative disease.

      Maes, T; Mascaró, C; Ortega, A; Lunardi, S; Ciceri, F; Somervaille, Tim C P; Buesa, C; Oryzon Genomics S.A., Carrer Sant Ferran 74, 08940 Cornella de Llobregat, Barcelona, (2015-06)
      Histone methylation and demethylation are important processes associated with the regulation of gene transcription, and alterations in histone methylation status have been linked to a large number of human diseases. Initially thought to be an irreversible process, histone methylation is now known to be reversed by two families of proteins containing over 30 members that act to remove methyl groups from specific lysine residues present in the tails of histone H3 and histone H4. A rapidly growing number of reports have implicated the FAD-dependent lysine specific demethylase (KDM1) family in cancer, and several small-molecule inhibitors are in development for the treatment of cancer. An additional role has emerged for KDM1 in brain function, offering additional opportunities for the development of novel therapeutic strategies in neurodegenerative disease. A decade after the identification of KDM1A as a histone demethylase, the first selective inhibitors have now reached the clinic.
    • KDM4B is a master regulator of the estrogen receptor signalling cascade.

      Gaughan, L; Stockley, J; Coffey, K; O'Neill, D; Jones, D; Wade, M; Wright, J; Moore, M; Tse, S; Rogerson, Lynsey; et al. (2013-08-01)
      The importance of the estrogen receptor (ER) in breast cancer (BCa) development makes it a prominent target for therapy. Current treatments, however, have limited effectiveness, and hence the definition of new therapeutic targets is vital. The ER is a member of the nuclear hormone receptor superfamily of transcription factors that requires co-regulator proteins for complete regulation. Emerging evidence has implicated a small number of histone methyltransferase (HMT) and histone demethylase (HDM) enzymes as regulators of ER signalling, including the histone H3 lysine 9 tri-/di-methyl HDM enzyme KDM4B. Two recent independent reports have demonstrated that KDM4B is required for ER-mediated transcription and depletion of the enzyme attenuates BCa growth in vitro and in vivo. Here we show that KDM4B has an overarching regulatory role in the ER signalling cascade by controlling expression of the ER and FOXA1 genes, two critical components for maintenance of the estrogen-dependent phenotype. KDM4B interacts with the transcription factor GATA-3 in BCa cell lines and directly co-activates GATA-3 activity in reporter-based experiments. Moreover, we reveal that KDM4B recruitment and demethylation of repressive H3K9me3 marks within upstream regulatory regions of the ER gene permits binding of GATA-3 to drive receptor expression. Ultimately, our findings confirm the importance of KDM4B within the ER signalling cascade and as a potential therapeutic target for BCa treatment.
    • Keratinocyte cancer excisions in Australia: who performs them and associated costs

      Thompson, BS; Pandeya, N; Olsen, CM; Dusingize, JC; Green, Adèle C; Neale, RE; Whiteman, DC; Department of Population Health, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (2019)
      BACKGROUND/OBJECTIVE: To describe the clinical settings in which keratinocyte cancers are excised in Queensland and describe the types of practitioners who excise them; to examine costs; and to identify predictors of hospital admission. METHODS: We used linked data for participants from the QSkin study (n = 43 794), including Medicare claims and Queensland hospital admissions relating to treatment episodes for incident keratinocyte cancers from July 2011 to June 2015. We used multinomial logistic regression to measure associations between demographic and clinical characteristics and treatment setting. The median costs of Medicare claims (AU$) were calculated. RESULTS: During 4 years of follow-up, there were 18 479 skin cancer excision episodes among 8613 people. Most excisions took place in private clinical rooms (89.7%), the remainder in hospitals (7.9% private; 2.4% public). Compared with other anatomical sites, skin cancers on the nose, eyelid, ear, lip, finger or genitalia were more likely to be treated in hospitals than in private clinical rooms (public hospital OR 5.7; 95%CI 4.5-7.2; private hospital OR 8.3; 95%CI 7.3-9.4). Primary care practitioners excised 83% of keratinocyte cancers, followed by plastic surgeons (9%) and dermatologists (6%). The median Medicare benefit paid was $253 in private clinical rooms and $334 in private hospitals. Out-of-pocket payments by patients treated in private hospitals were fourfold higher than those in private clinical rooms ($351 vs $80). CONCLUSIONS: Most keratinocyte cancers are excised in primary care, although more than 10% of excisions occur in hospital settings.
    • Keratinocyte carcinomas: current concepts and future research priorities

      Nagarajan, P; Asgari, MM; Green, Adèle C; Guhan, SM; Arron, ST; Proby, CM; Rollison, DE; Harwood, CA; Toland, AE; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (2019)
      Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) are keratinocyte carcinomas, the most frequently diagnosed cancers in fair-skinned populations. Ultraviolet radiation (UVR) is the main driving carcinogen for these tumors, but immunosuppression, pigmentary factors, and aging are also risk factors. Scientific discoveries have improved the understanding of the role of human papillomaviruses (HPV) in cSCC as well as the skin microbiome and a compromised immune system in the development of both cSCC and BCC. Genomic analyses have uncovered genetic risk variants, high-risk susceptibility genes, and somatic events that underlie common pathways important in keratinocyte carcinoma tumorigenesis and tumor characteristics that have enabled development of prediction models for early identification of high-risk individuals. Advances in chemoprevention in high-risk individuals and progress in targeted and immune-based treatment approaches have the potential to decrease the morbidity and mortality associated with these tumors. As the incidence and prevalence of keratinocyte carcinoma continue to increase, strategies for prevention, including effective sun-protective behavior, educational interventions, and reduction of tanning bed access and usage, are essential. Gaps in our knowledge requiring additional research to reduce the high morbidity and costs associated with keratinocyte carcinoma include better understanding of factors leading to more aggressive tumors, the roles of microbiome and HPV infection, prediction of response to therapies including immune checkpoint blockade, and how to tailor both prevention and treatment to individual risk factors and needs.
    • Keratinocyte growth factor increases hair follicle survival following cytotoxic insult.

      Booth, Catherine; Potten, Christopher S; CRC Epithelial Biology Group, Paterson Institute, Christie Hospital (NHS) Trust, Manchester, U.K. cbooth@picr.man.ac.uk (2000-04)
      Hair loss is a distressing side-effect of cancer therapy. Factors that might reduce this loss are therefore likely to improve patient well-being and reduce treatment refusal. Keratinocyte growth factor has been shown to regulate proliferation and differentiation in epithelial tissues and may regulate the clonogenic cells (stem cells) of the hair follicle. Using X-irradiation as a model cytotoxic agent we investigated whether keratinocyte growth factor pretreatment could increase hair follicle survival (by implication clonogen survival) and regeneration of differentiated progeny (a hair). Irradiated telogen follicle survival data were consistent with that published previously. Daily keratinocyte growth factor pretreatment increased hair survival during the first hair growth cycle, the level of protection having a slight radiation dose dependence. Protection was maintained after a second hair cycle, but at a lower level (hairs and follicles). Hairs irradiated in anagen and analyzed during the second cycle exhibited a similar level of protection. No difference in protection levels could be observed between mice treated either once or twice daily with keratinocyte growth factor. Results indicated approximately 10 extra hairs per mm2 (14.5% of unirradiated control) could survive the cytotoxic insult if pretreated with 12.5 microg keratinocyte growth factor. This could be doubled by a 10 x higher keratinocyte growth factor dose. The fact that protection was maintained during two cycles of hair growth indicated that the clonogenic cells had been protected. Keratinocyte growth factor pretreatment had no significant effect on the level of mitosis but increased the number of p21waf1 expressing cells. Intriguingly, the number of apoptotic fragments per follicle were transiently increased in the keratinocyte growth factor pretreated mice, although this effect was most pronounced in the upper half of the follicle bulb, i.e., above (rather than within) the germinal matrix.
    • Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality.

      Farrell, C L; Bready, J V; Rex, K L; Chen, J N; DiPalma, C R; Whitcomb, K L; Yin, S; Hill, D C; Wiemann, B; Starnes, C O; et al. (1998-03-01)
      Keratinocyte growth factor (KGF) stimulates the proliferation and differentiation of epithelial cells including those of the gastrointestinal tract. Although chemotherapeutics and radiation exposure kill rapidly proliferating tumor cells, rapidly dividing normal cells of the host's gastrointestinal tract are also frequently damaged, leading to the clinical condition broadly termed "mucositis." In this report, recombinant human KGF used as a pretreatment in several mouse models of chemotherapy and/or radiation-induced gastrointestinal injury significantly improved mouse survival. Using multiple-dose 5-fluorouracil, methotrexate, and radiation in combination and total body radiation alone models, KGF increased survival by 55% or greater. In the models that used chemotherapy with or without radiation, KGF significantly ameliorated weight loss after injury and accelerated weight gain during recovery. The basis of these systemic benefits appears to be due in part to the trophic effects of the growth factor on the intestinal epithelium because KGF pretreatment caused an increase in measures of mucosal thickness (villus height and crypt depth) that persisted during the course of 5-fluorouracil chemotherapy. Treatment with KGF also afforded a 3.5-fold improvement in crypt survival in the small intestine, suggesting that KGF also has a direct effect on the crypt stem cells. These data indicate that KGF may be therapeutically useful to lessen the intestinal side effects of current cancer therapy regimens.
    • Keratinocyte proliferative hierarchies confer protective mechanisms in surface epithelia.

      Hume, W J; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester M20 9BX, England. (1985-04)
    • Keratinocyte stem cells: a commentary.

      Potten, Christopher S; Booth, Catherine; Epithelial Biology Department, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, U.K. c.potten@epistem.co.uk (2002-10)
      For many years it has been widely accepted that stem cells play a crucial role in adult tissue maintenance. The concept that the renewing tissues of the body contain a small subcompartment of self-maintaining stem cells, upon which the entire tissue is dependent, is also now accepted as applicable to all renewing tissues. Gene therapy and tissue engineering are driving considerable interest in the clinical application of such hierarchically organized cellular compartments. Recent initial observations have provided a tantalizing insight into the large pluripotency of these cells. Indeed, scientists are now beginning to talk about the possible totipotency of some adult tissue stem cells. Such work is currently phenomenologic, but analysis of data derived from genomics and proteomics, identifying the crucial control signals involved, will soon provide a further impetus to stem cell biology with far reaching applications. The epidermis with its relatively simple structure, ease of accessibility, and the ability to grow its cells in vitro is one obvious target tissue for testing stem cell manipulation theories. It is crucial, however, that the normal keratinocyte stem cell is thoroughly characterized prior to attempting to manipulate its pluripotency. This commentary assesses the data generated to date and critically discusses the conclusions that have been drawn. Our current level of understanding, or lack of understanding, of the keratinocyte stem cell is reviewed.
    • Ketones and lactate "fuel" tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism.

      Bonuccelli, G; Tsirigos, A; Whitaker-Menezes, D; Pavlides, S; Pestell, R G; Chiavarina, B; Frank, P G; Flomenberg, N; Howell, Anthony; Martinez-Outschoorn, U E; et al. (2010-09)
      Previously, we proposed a new model for understanding the "Warburg effect" in tumor metabolism. In this scheme, cancer-associated fibroblasts undergo aerobic glycolysis and the resulting energy-rich metabolites are then transferred to epithelial cancer cells, where they enter the TCA cycle, resulting in high ATP production via oxidative phosphorylation. We have termed this new paradigm "The Reverse Warburg Effect." Here, we directly evaluate whether the end-products of aerobic glycolysis (3-hydroxy-butyrate and L-lactate) can stimulate tumor growth and metastasis, using MDA-MB-231 breast cancer xenografts as a model system. More specifically, we show that administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by ∼2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. Both 3-hydroxy-butyrate and L-lactate functioned as chemo-attractants, stimulating the migration of epithelial cancer cells. Although L-lactate did not increase primary tumor growth, it stimulated the formation of lung metastases by ∼10-fold. Thus, we conclude that ketones and lactate fuel tumor growth and metastasis, providing functional evidence to support the "Reverse Warburg Effect". Moreover, we discuss the possibility that it may be unwise to use lactate-containing i.v. solutions (such as Lactated Ringer's or Hartmann's solution) in cancer patients, given the dramatic metastasis-promoting properties of L-lactate. Also, we provide evidence for the up-regulation of oxidative mitochondrial metabolism and the TCA cycle in human breast cancer cells in vivo, via an informatics analysis of the existing raw transcriptional profiles of epithelial breast cancer cells and adjacent stromal cells. Lastly, our findings may explain why diabetic patients have an increased incidence of cancer, due to increased ketone production, and a tendency towards autophagy/mitophagy in their adipose tissue.
    • Ketones and lactate increase cancer cell "stemness," driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via Metabolo-Genomics.

      Martinez-Outschoorn, U E; Prisco, M; Ertel, A; Tsirigos, A; Lin, Z; Pavlides, S; Wang, C; Flomenberg, N; Knudsen, E S; Howell, Anthony; et al. (2011-04-15)
      Previously, we showed that high-energy metabolites (lactate and ketones) "fuel" tumor growth and experimental metastasis in an in vivo xenograft model, most likely by driving oxidative mitochondrial metabolism in breast cancer cells. To mechanistically understand how these metabolites affect tumor cell behavior, here we used genome-wide transcriptional profiling. Briefly, human breast cancer cells (MCF7) were cultured with lactate or ketones, and then subjected to transcriptional analysis (exon-array). Interestingly, our results show that treatment with these high-energy metabolites increases the transcriptional expression of gene profiles normally associated with "stemness," including genes upregulated in embryonic stem (ES) cells. Similarly, we observe that lactate and ketones promote the growth of bonafide ES cells, providing functional validation. The lactate- and ketone-induced "gene signatures" were able to predict poor clinical outcome (including recurrence and metastasis) in a cohort of human breast cancer patients. Taken together, our results are consistent with the idea that lactate and ketone utilization in cancer cells promotes the "cancer stem cell" phenotype, resulting in significant decreases in patient survival. One possible mechanism by which these high-energy metabolites might induce stemness is by increasing the pool of Acetyl-CoA, leading to increased histone acetylation, and elevated gene expression. Thus, our results mechanistically imply that clinical outcome in breast cancer could simply be determined by epigenetics and energy metabolism, rather than by the accumulation of specific "classical" gene mutations. We also suggest that high-risk cancer patients (identified by the lactate/ketone gene signatures) could be treated with new therapeutics that target oxidative mitochondrial metabolism, such as the anti-oxidant and "mitochondrial poison" metformin. Finally, we propose that this new approach to personalized cancer medicine be termed "Metabolo-Genomics," which incorporates features of both 1) cell metabolism and 2) gene transcriptional profiling. Importantly, this powerful new approach directly links cancer cell metabolism with clinical outcome, and new therapeutic strategies for inhibiting the TCA cycle and mitochondrial oxidative phosphorylation in cancer cells.
    • A key role for Ctf4 in coupling the MCM2-7 helicase to DNA polymerase alpha within the eukaryotic replisome.

      Gambus, Agnieszka; Van Deursen, Frederick; Polychronopoulos, Dimitrios; Foltman, Magdalena; Jones, Richard C; Edmondson, Ricky D; Calzada, Arturo; Labib, Karim; Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK. (2009-10-07)
      The eukaryotic replisome is a crucial determinant of genome stability, but its structure is still poorly understood. We found previously that many regulatory proteins assemble around the MCM2-7 helicase at yeast replication forks to form the replisome progression complex (RPC), which might link MCM2-7 to other replisome components. Here, we show that the RPC associates with DNA polymerase alpha that primes each Okazaki fragment during lagging strand synthesis. Our data indicate that a complex of the GINS and Ctf4 components of the RPC is crucial to couple MCM2-7 to DNA polymerase alpha. Others have found recently that the Mrc1 subunit of RPCs binds DNA polymerase epsilon, which synthesises the leading strand at DNA replication forks. We show that cells lacking both Ctf4 and Mrc1 experience chronic activation of the DNA damage checkpoint during chromosome replication and do not complete the cell cycle. These findings indicate that coupling MCM2-7 to replicative polymerases is an important feature of the regulation of chromosome replication in eukaryotes, and highlight a key role for Ctf4 in this process.
    • A key role for the GINS complex at DNA replication forks

      Labib, Karim; Gambus, Agnieszka; Cancer Research U.K., Paterson Institute for Cancer Research, University of Manchester, Manchester, UK. klabib@picr.man.ac.uk <klabib@picr.man.ac.uk> (2007-06)
      The GINS complex is the most recently identified component of the eukaryotic DNA replication machinery and is required both for the initiation of chromosome replication and also for the normal progression of DNA replication forks. Several recent studies suggest that GINS associates at replication forks with the MCM helicase that is responsible for unwinding the parental DNA duplex. Archaea also have an equivalent GINS complex that can interact with MCM and other replisome components. It seems likely that GINS couples MCM to other key proteins at forks, and we discuss here the current literature regarding this important late-comer to the DNA replication field.
    • Key steps in vaccine development

      Stern, Peter L; University of Manchester, UK (2020)
      OBJECTIVE: The goal of a vaccine is to prime the immune response so the immune memory can facilitate a rapid response to adequately control the pathogen on natural infection and prevent disease manifestation. This article reviews the main elements that provide for the development of safe and effective vaccines Data Sources: Literature covering target pathogen epidemiology, the key aspects of the functioning immune response underwriting target antigen selection, optimal vaccine formulation, preclinical and clinical trial studies necessary to deliver safe and efficacious immunization. STUDY SELECTIONS: Whole live, inactivated, attenuated or partial fractionated organism based vaccines are discussed in respect of the balance of reactogenicity and immunogenicity. The use of adjuvants to compensate for reduced immunogenicity is described. The requirements from preclinical studies, including establishing a proof of principle in animal models, the design of clinical trials with healthy volunteers that that lead to licensure and beyond are reviewed. RESULTS: The three vaccine development phases, preclinical, clinical and post licensure integrate the requirements to ensure safety, immunogenicity and efficacy in the final licensed product. Continuing monitoring of efficacy and safety in the immunized populations is essential to sustain confidence in vaccination programs. CONCLUSION: In an era of increasing vaccine hesitancy the need for a better and widespread understanding of how immunization acts to counteract the continuing and changing risks from the pathogenic world is required. This demands a societal responsibility for obligate education on the benefits of vaccination, which as a medical intervention has saved more lives than any other procedure.
    • KEYNOTE-966 trial in progress: Pembrolizumab plus gemcitabine and cisplatin for advanced biliary tract cancer

      Valle, Juan W; Kelley, R. K.; Furuse, J.; Edeline, J.; Finn, R. S.; Ren, Z.; Su, S. C.; Malhotra, U.; Siegel, A. B.; Vogel, A.; et al. (2020)
      Background: Biliary tract cancer (BTC), comprising intra- and extra-hepatic cholangiocarcinoma and gallbladder cancer, is a rare and aggressive malignancy. Most patients (pts) present with advanced or unresectable disease, for which the current standard of care is gemcitabine plus cisplatin. Median survival for these pts is only 12 months, highlighting the need for more effective therapies. Pembrolizumab is a PD-1inhibitor that has demonstrated modest antitumor activity as monotherapy in pts with previously treated BTC and has improved survival when used in combination with platinum-based chemotherapy in other cancer types.
    • Kin4 kinase delays mitotic exit in response to spindle alignment defects.

      Pereira, Gislene; Schiebel, Elmar; Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK. gislene.pereira@manchester.ac.uk (2005-07-22)
      For many polarized cells, it is critical that the mitotic spindle becomes positioned relative to the polarity axis. This is especially important in yeast, where the site of cytokinesis is predetermined. The spindle position checkpoint (SPOC) therefore delays mitotic exit of cells with a mispositioned spindle. One component of the SPOC is the Bub2-Bfa1 complex, an inhibitor of the mitotic exit network (MEN). Here, we show that the Kin4 kinase is a component of the SPOC and as such is essential to delay cell cycle progression of cells with a misaligned spindle. When spindles are correctly oriented, Kin4 and Bub2-Bfa1 are asymmetrically localized to opposite spindle pole bodies (SPBs). Bub2-Bfa1 then becomes inhibited by Cdc5 polo kinase with anaphase onset, a prerequisite for mitotic exit. In response to spindle misalignment, Kin4 and Bub2-Bfa1 are brought together at both SPBs. Kin4 now maintains Bub2-Bfa1 activity by counteracting Cdc5, thereby inhibiting mitotic exit.