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I Hoffmann

Publications and source records attributed to I Hoffmann.

At least 37 records · Page 2Linked to original sources
PubMed2000

Seven genes that are differentially transcribed in colorectal tumor cell lines.

To identify genes which are differentially transcribed in colorectal tumor cells, we compared the two human tumor cell lines, SW480 and HCT116, with the cell line, NCM460, from normal colon epithelium as a control. Using the methods of differential display reverse transcription PCR and Northern blot hybridization, we detected the differential transcription of seven genes: cholecystokinin, reticulocalbin, Rab5 guanine nucleotide exchange factor Rabex5, caldesmon, differentiation related gene 1 (drg1), taxol resistant associated gene 3 (Trag-3) and the gene for the placental protein, diff33. The yet unidentified cDNA of the human Rabex5 gene and the 3' untranslated region of the human caldesmon gene were cloned.

Amino Acid Sequence↗
PubMed2000

A new therapeutic option by subcutaneous recombinant hirudin in patients with heparin-induced thrombocytopenia type II: a pilot study.

We prospectively studied 15 patients suffering from acute heparin-induced thrombocytopenia (HIT) type II with and without thromboembolic events and 4 patients with anamnestically known HIT type II recurrently requiring thromboprophylaxis in order to develop new therapeutic strategies by subcutaneous recombinant hirudin administration. Patients with acute venous or arterial thromboembolism were treated with aPTT-controlled intravenous (mean: 19.3 days) followed by subcutaneous r-hirudin (mean: 22.5 days). Patients without thromboembolism were treated with subcutaneous r-hirudin (mean: 25.9 days). Four patients were readmitted to subcutaneous r-hirudin (mean: 32 days). When r-hirudin was administered subcutaneously following intravenous treatment, mean baseline (prior to the injection) and mean peak (1.5-2.5 hours after the injection) aPTT ratios were 1.1 (+/-0.2) to 1.7 (+/-0.48) and 2. 48 (+/-0.43) to 2.52 (+/-0.4) times normal value, respectively. Mean baseline and mean peak ECT ratios were 1.2 (+/-0.12) to 1.9 (+/-0. 22) and 2.2 (+/-0.25) to 2.6 (+/-0.11) times the upper normal value, respectively. When r-hirudin was initially administered subcutaneously, mean baseline and mean peak aPTT ratios were 1.41 (+/-0.25) to 1.61 (+/-00.28) and 1.88 (+/-0.26) to 2.06 (+/-0.09) times the normal value, respectively. Mean baseline and mean peak ECT ratios were 1.25 (+/-0.2) to 1.5 (+/-0.38) and 2.01 (+/-0.21) to 2.23 (+/-0.25) times the upper limit of normal, respectively. Patients who received recurrent subcutaneous r-hirudin had mean baseline and peak aPTT values of 1.5 (+/-0.35) to 1.75 (+/-0.156) and 2.0 (+/-0.33) to 2.1 (+/-0.18) times the normal value, respectively. Mean baseline and peak ECT ratios were 1.3 (+/-0.26) to 1.65 (+/-0.09) and 1.94 (+/-0.256) to 2.7 (+/-0.23) times the upper limit of normal, respectively. The overall cumulative incidence of r-hirudin antibodies was 12/19 (63%) with a significant accumulation of r-hirudin in antibody-positive patients compared to antibody-negative patients (p<0.05). No patient suffered a new thromboembolic or major bleeding event. Subcutaneous administration of recombinant hirudin provides a long-term thromboprophylaxis regimen in HIT type II patients after passivation of acute thromboembolism.

Adult↗
PubMed2000

[Prevention of thrombosis with subcutaneous recombinant hirudin in heparin-induced thrombocytopenia type II. A pilot study].

BACKGROUND: Heparin-induced thrombocytopenia (HIT) type II is a severe complication of heparin therapy with a high incidence of thromboembolic events. AIM: The aim of this prospective study was to evaluate efficacy and safety of prophylaxis of thromboembolism with subcutaneous r-hirudin (25 mg twice daily) in patients with HIT type II. PATIENTS AND METHODS: From 01/06/1997 until 01/08/1999, 19 patients were prospectively included into the study. During subcutaneous r-hirudin application (25 mg twice daily) the activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT) were measured twice daily prior to and 2 hours after the morning injection. RESULTS: Ten patients (mean age: 68 years; two men, eight women) with thromboembolic events were intravenously treated with r-hirudin (mean 19.3 days) with a target aPTT of 1.5 to 2.5 times normal values followed by subcutaneous r-hirudin (mean 22.5 days). Five Patients without thromboembolism immediately received subcutaneous r-hirudin (mean 25.9 days; mean age: 61 jahre; two men, three women) after cessation of heparin. Four patients requiring prophylaxis of thromboembolism received subcutaneous r-hirudin (mean 32 days; mean age: 68 years; four women) because of HIT type II in the past. Mean aPTT-values prior to and 1.5-2.5 hours after the morning injection were 1.2 to 1.7 and 2.0 to 2.3 times normal values, respectively. The ECT was prolonged by 1.2 to 1.7 and 2.3 to 2.5 times the upper normal value, respectively. Thromboembolic or bleeding events were not observed during the study. CONCLUSION: The subcutaneous application of r-hirudin provides an alternative for primary and secondary prophylaxis of thromboembolism in HIT type II patients.

Aged↗
PubMed2000

Phosphorylation of FADD/ MORT1 at serine 194 and association with a 70-kDa cell cycle-regulated protein kinase.

The adapter molecule Fas-associated death domain protein (FADD)/mediator of receptor-induced toxicity-1 (MORT1) is essential for signal transduction of the apoptosis-inducing receptor CD95 (APO-1/Fas) as it connects the activated receptor with the effector caspase-8. FADD also plays a role in embryonic development and the cell cycle reentry of T cells. FADD is phosphorylated at serine residues. We now show that phosphorylation exclusively occurs at serine 194. The phosphorylation of FADD was found to correlate with the cell cycle. In cells arrested at the G2/M boundary with nocodazole, FADD was quantitatively phosphorylated, whereas only nonphosphorylated FADD was found in cells arrested in G1/S with hydroxyurea. In this context, we have identified a 70-kDa cell cycle-regulated kinase that specifically binds to the C-terminal half of FADD. Because CD95-mediated apoptosis is independent of the cell cycle, phosphorylation of FADD may regulate its apoptosis-independent functions.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Cell cycle regulation by the Cdc25 phosphatase family.

Activation of cyclin-dependent kinases in higher eukaryotic cells can be achieved through dephosphorylation by members of the Cdc25 phosphatase family, Cdc25A, Cdc25B and Cdc25C. Cdc25A plays an important role at the G1/S-phase transition. Cdc25B undergoes activation during S-phase and plays a role in activating the mitotic kinase Cdk1/cyclin B in the cytoplasm. Active Cdk1/cyclin B then phosphorylates and activates Cdc25C leading to a positive feedback mechanism and to entry into mitosis. Cdc25A and B are potential human oncogenes. In addition, Cdc25 is a main player of the G2 arrest caused by DNA damage or in the presence of unreplicated DNA.

Catalysis↗
PubMed1999

The physical association and phosphorylation of Cdc25C protein phosphatase by Prk.

prk encodes a protein serine/threonine kinase involved in regulating M phase functions during the cell cycle. We have expressed His6-Prk and His6-Cdc25C proteins using the baculoviral vector expression system. Purified recombinant His6-Prk, but not a kinase-defective mutant His6-PrkK52R, is capable of strongly phosphorylating His6-Cdc25C in vitro. Co-immunoprecipitation and affinity column chromatography experiments demonstrate that GST-Prk and native Cdc25C interact. When co-infected with His6-Prk and His6-Cdc25C recombinant baculoviruses, sf-9 cells produce His6-Cdc25C antigen with an additional slower mobility band on denaturing polyacrylamide gels compared with cells infected with His6-Cdc25C baculovirus alone. In addition, His6-Cdc25C immunoprecipitated from sf-9 cells co-infected with His6-Prk and His6-Cdc25C baculoviruses, but not with His6-PrkK52R and His6-Cdc25C baculoviruses, contains a greatly enhanced kinase activity that phosphorylates His6-Cdc25C in vitro. Moreover, phosphopeptide mapping shows that His6-Prk phosphorylates His6-Cdc25C at two sites in vitro and that the major phosphorylation site co-migrates with the one that is phosphorylated in vivo in asynchonized cells. Further studies reveal that His6-Prk phosphorylates Cdc25C on serine216, a residue also phosphorylated by Chk1 and Chk2. Together, these observations strongly suggest that Prk's role in mitosis is at least partly mediated through direct regulation of Cdc25C.

Animals↗
PubMed1999

The APC protein binds to A/T rich DNA sequences.

The tumor suppressor protein APC (Adenomatous Polyposis Coli) is localized in the cytosol and in the nucleus. In this study, we demonstrate that the nuclear APC protein level is high in cells in the basal crypt region of the normal colorectal epithelium. Strikingly, the APC protein staining resembles the staining pattern of a nuclear proliferation marker. As a first step towards a possible role of the nuclear APC protein, we provide data showing the direct interaction of the nuclear APC protein with DNA. A nuclear APC isoform precipitates with matrix-immobilized DNA. Vice versa, the immunoprecipitation of APC from nuclear lysates results in co-precipitation of genomic DNA. Using recombinant APC fragments we mapped three DNA binding domains: one within the beta-catenin binding and regulatory domain, and two in the carboxyterminal third of the APC protein. All these three domains contain clusters of repetitive S(T)PXX sequence motifs that were described to mediate the DNA interaction of many other DNA binding proteins. In analogy to S(T)PXX proteins, the APC protein binds preferentially to A/T rich DNA sequences rather than to a single DNA sequence motif.

Adenomatous Polyposis Coli↗
PubMed1999

[Non-invasive management of multiple brain abscesses. Case report and review of the literature].

The authors report a case and treatment of multiple brain abscesses located in the cerebrum and cerebellum combined with subdural empyema. In conjunction with the case report, the authors review the literature on the pathogenesis of brain abscesses and discuss therapeutic strategies concerning the topic. In the case presented, the primary infection persisted in the lung causing subclinical bronchitis. The hemoculture showed evidence of Streptococcus mitis infection. Although the etiological role of this bacterium in meningitis is known, it rarely causes bacterial meningitis without underlying predisposing factors. In their case, the patient was free of the most common predisposing factors such as congenital heart disease or immunodeficiency. Following the 2 month period of latency, a rapid onset of the symptoms of intracranial inflammation could be observed: fever, headache, meningeal symptoms, focal neurological symptoms and coma. They were not able to identify any bacteria in the cerebrospinal fluid; the Streptocossus mitis could be cultivated only from the haemoculture. The cytological analysis of the cerebrospinal fluid showed typical signs of bacterial infection and the cranial Computed Tomography revealed multiple cerebral abscesses. Neurosurgical intervention was not recommended because of the number, localization and size of the focal lesions. The therapy consisted of intravenous administration of 24 x 10(6) IU/die Penicillin and 4 g/die ceftriaxon. For supportive therapy, Mannitol B, 3 mg/die clonazepam and 300 mg/die phenytoin were administered. Corticosteroids were not used during the course of therapy. Two years later the 55 year old female is symptom free and doing well.

Brain Abscess↗
PubMed1999

Cdc25B and Cdc25C differ markedly in their properties as initiators of mitosis.

We have used time-lapse fluorescence microscopy to study the properties of the Cdc25B and Cdc25C phosphatases that have both been implicated as initiators of mitosis in human cells. To differentiate between the functions of the two proteins, we have microinjected expression constructs encoding Cdc25B or Cdc25C or their GFP-chimeras into synchronized tissue culture cells. This assay allows us to express the proteins at defined points in the cell cycle. We have followed the microinjected cells by time-lapse microscopy, in the presence or absence of DNA synthesis inhibitors, and assayed whether they enter mitosis prematurely or at the correct time. We find that overexpressing Cdc25B alone rapidly causes S phase and G2 phase cells to enter mitosis, whether or not DNA replication is complete, whereas overexpressing Cdc25C does not cause premature mitosis. Overexpressing Cdc25C together with cyclin B1 does shorten the G2 phase and can override the unreplicated DNA checkpoint, but much less efficiently than overexpressing Cdc25B. These results suggest that Cdc25B and Cdc25C do not respond identically to the same cell cycle checkpoints. This difference may be related to the differential localization of the proteins; Cdc25C is nuclear throughout interphase, whereas Cdc25B is nuclear in the G1 phase and cytoplasmic in the S and G2 phases. We have found that the change in subcellular localization of Cdc25B is due to nuclear export and that this is dependent on cyclin B1. Our data suggest that although both Cdc25B and Cdc25C can promote mitosis, they are likely to have distinct roles in the controlling the initiation of mitosis.

Biological Transport↗
PubMed1999

Molecular analysis of two closely related mouse aldehyde dehydrogenase genes: identification of a role for Aldh1, but not Aldh-pb, in the biosynthesis of retinoic acid.

Mammalian class I aldehyde dehydrogenase (ALDH1) has been implicated as a retinal dehydrogenase in the biosynthesis of retinoic acid, a modulator of gene expression and cell differentiation. As the first step towards studying the regulation of ALDH1 and its physiological role in the biosynthesis of retinoic acid, mouse ALDH1 cDNA and genomic clones have been characterized. During the cloning process, an additional closely related gene was also isolated and named Aldh-pb, owing to its high amino acid sequence identity (92%) with the rat phenobarbitol-inducible ALDH protein (ALDH-PB). Aldh1 spans about 45 kb in length, whereas Aldh-pb spans about 35 kb. Both genes are composed of 13 exons, and the positions of all the exon/intron boundaries are conserved with those of human ALDH1. The promoter regions of Aldh1 and Aldh-pb demonstrate high sequence similarity with those of human ALDH1 and rat ALDH-PB. Expression of Aldh1 and Aldh-pb is tissue-specific, with mRNAs for both genes being found in the liver, lung and testis, but not in the heart, spleen or muscle. Expression of Aldh-pb, but not Aldh1, was also detected at high levels in the kidney. Aldh1 and Aldh-pb encode proteins of 501 amino acids with 90% positional identity. To examine the relative roles of these two enzymes in retinoic acid synthesis in vivo, Xenopus embryos were injected with mRNAs encoding these enzymes to assay the effect on conversion of endogenous retinal into retinoic acid. Injection of ALDH1, but not ALDH-PB, mRNA stimulated retinoic acid synthesis in Xenopus embryos at the blastula stage. Thus our results indicate that Aldh1 can function in retinoic acid synthesis under physiological conditions, but that the closely related Aldh-pb does not share this property.

Aldehyde Dehydrogenase↗
PubMed1999

Cadherin-11 is highly expressed in rhabdomyosarcomas and during differentiation of myoblasts in vitro.

Rhabdomyosarcomas bear a morphological and genetic resemblance to developing skeletal muscle. Apart from myogenic marker genes (bHLH factors, myosin, actin), cell adhesion molecules such as N-cadherin and N-CAM have been reported to be expressed both in rhabdomyosarcomas and during myogenesis. The present study demonstrates the expression of another cadherin, cadherin-11, in rhabdomyosarcomas and during differentiation of myoblasts in vitro: cadherin-11, a predominantly mesenchymal cell adhesion molecule, is highly expressed in embryonal rhabdomyosarcomas and alveolar rhabdomyosarcomas, which do not bear the Pax-3-FKHR fusion previously described. Cadherin-11 is down-regulated in normal skeletal muscle and after myotube formation in vitro. The results of this study suggest that cadherin-11 might be involved in myogenesis and that rhabdomyosarcomas may re-express or fail to down-regulate cadherin-11. Since alveolar rhabdomyosarcomas bearing the t(2;13) translocation do not express cadherin-11, it is postulated that Pax-3 and cadherin-11 might be linked and involved in the same myogenic pathway.

Animals↗
PubMed1999

Distinct functions for Aldh1 and Raldh2 in the control of ligand production for embryonic retinoid signaling pathways.

During vertebrate embryogenesis retinoic acid (RA) synthesis must be spatiotemporally regulated in order to appropriately stimulate various retinoid signaling pathways. Various forms of mammalian aldehyde dehydrogenase (ALDH) have been shown to oxidize the vitamin A precursor retinal to RA in vitro. Here we show that injection of Xenopus embryos with mRNAs for either mouse Aldh1 or mouse Raldh2 stimulates RA synthesis at low and high levels, respectively, while injection of human ALDH3 mRNA is unable to stimulate any detectable level of RA synthesis. This provides evidence that some members of the ALDH gene family can indeed perform RA synthesis in vivo. Whole-mount immunohistochemical analyses of mouse embryos indicate that ALDH1 and RALDH2 proteins are localized in distinct tissues. RALDH2 is detected at E7.5-E10.5 primarily in trunk tissue (paraxial mesoderm, somites, pericardium, midgut, mesonephros) plus transiently from E8.5-E9.5 in the ventral optic vesicle and surrounding frontonasal region. ALDH1 is first detected at E9.0-E10. 5 primarily in cranial tissues (ventral mesencephalon, dorsal retina, thymic primordia, otic vesicles) and in the mesonephros. As previous findings indicate that embryonic RA is more abundant in trunk rather than cranial tissues, our findings suggest that Raldh2 and Aldh1 control distinct retinoid signaling pathways by stimulating high and low RA biosynthetic activities, respectively, in various trunk and cranial tissues.

Aldehyde Dehydrogenase↗
PubMed1999

Immunohistological analysis of E-cadherin, alpha-, beta- and gamma-catenin expression in colorectal cancer: implications for cell adhesion and signaling.

Intercellular adhesion mediated by the E-cadherin/catenin complex is a prerequisite for epithelial integrity and differentiation. In carcinomas, E-cadherin function is frequently disturbed, and has been suggested to increase invasion and metastasis of tumour cells. beta-catenin has also been implicated in signaling pathways essential for tumour formation. We analysed the E-cadherin/catenin adhesion system of colorectal tumours at different clinical stages. In primary carcinomas (n = 91), there was a frequent reduction in E-cadherin (44%) and alpha-catenin expression (36%). In contrast, beta-catenin and gamma-catenin expression were seldom reduced (4% and 15%, respectively). Similar expression patterns were observed in liver metastases from unrelated colorectal tumours (n = 27). There was a significant relationship between loss of E-cadherin and alpha-catenin expression and poorly differentiated (G3-4) tumours. Our results suggest that reduction of E-cadherin/alpha-catenin expression is a frequent event in primary and metastatic colorectal carcinomas. Furthermore, beta-catenin expression remains normal in colorectal cancer, suggesting the essential role of beta-catenin in signaling pathways.

Cadherins↗
PubMed1999

Ectopic expression of Cdc25A accelerates the G(1)/S transition and leads to premature activation of cyclin E- and cyclin A-dependent kinases.

Human Cdc25 phosphatases play important roles in cell cycle regulation by removing inhibitory phosphates from tyrosine and threonine residues of cyclin-dependent kinases. Three human Cdc25 isoforms, A, B, and C, have been discovered. Cdc25B and Cdc25C play crucial roles at the G(2)/M transition. In the present study, we have investigated the function of human Cdc25A phosphatase. Cell lines that express human Cdc25A in an inducible manner have been generated. Ectopic expression of Cdc25A accelerates the G(1)/S-phase transition, indicating that Cdc25A controls an event(s) that is rate limiting for entry into S phase. Furthermore, we carried out a detailed analysis of the expression and activation of human Cdc25A. Activation of endogenous Cdc25A occurs during late G(1) phase and increases in S and G(2) phases. We further demonstrate that Cdc25A is activated at the same time as cyclin E- and cyclin A-dependent kinases. In vitro, Cdc25A dephosphorylates and activates the cyclin-Cdk complexes that are active during G(1). Overexpression of Cdc25A in the inducible system, however, leads to a premature activation of both cyclin E-Cdk2 and cyclin A-Cdk2 complexes, while no effect of cyclin D-dependent kinases is observed. Furthermore, Cdc25A overexpression induces a tyrosine dephosphorylation of Cdk2. These results suggest that Cdc25A is an important regulator of the G(1)/S-phase transition and that cyclin E- and cyclin A-dependent kinases act as direct targets.

Animals↗
PubMed1999

Consequences of a long-term raw food diet on body weight and menstruation: results of a questionnaire survey.

OBJECTIVE: To examine the relationship between the strictness of long-term raw food diets and body weight loss, underweight and amenorrhea. METHODS: In a cross-sectional study 216 men and 297 women consuming long-term raw food diets (3.7 years; SE 0.25) of different intensities completed a specially developed questionnaire. Participants were divided into 5 groups according to the amount of raw food in their diet (70-79, 80-89, 90-94, 95-99 and 100%). A multiple linear regression model (n = 513) was used to evaluate the relationship between body weight and the amount of raw food consumed. Odds of underweight were determined by a multinomial logit model. RESULTS: From the beginning of the dietary regimen an average weight loss of 9.9 kg (SE 0.4) for men and 12 kg (SE 0.6) for women was observed. Body mass index (BMI) was below the normal weight range (<18.5 kg/m(2)) in 14.7% of male and 25.0% of female subjects and was negatively related to the amount of raw food consumed and the duration of the raw food diet. About 30% of the women under 45 years of age had partial to complete amenorrhea; subjects eating high amounts of raw food (>90%) were affected more frequently than moderate raw food dieters. CONCLUSIONS: The consumption of a raw food diet is associated with a high loss of body weight. Since many raw food dieters exhibited underweight and amenorrhea, a very strict raw food diet cannot be recommended on a long-term basis.

Adult↗
PubMed1998

Alcohol dehydrogenases in Xenopus development: conserved expression of ADH1 and ADH4 in epithelial retinoid target tissues.

Mammalian alcohol dehydrogenases ADH1 (class I ADH) and ADH4 (class IV ADH) function as retinol dehydrogenases contributing to the synthesis of retinoic acid, the active form of vitamin A involved in growth and development. Xenopus laevis ADH1 and ADH4 genes were isolated using polymerase chain reaction primers corresponding to conserved motifs of vertebrate ADHs. The predicted amino acid sequence of Xenopus ADH1 was clearly found to be an ortholog of ADH1 from the related amphibian Rana perezi. Phylogenetic tree analysis of the Xenopus ADH4 sequence suggested this enzyme is likely to be an ADH4 ortholog, and this classification was more confidently made when based also on the unique expression patterns of Xenopus ADH1 and ADH4 in several retinoid-responsive epithelial tissues. Northern blot analysis of Xenopus adult tissues indicated nonoverlapping patterns of ADH expression, with ADH1 mRNA found in small intestine, large intestine, liver, and mesonephros and ADH4 mRNA found in esophagus, stomach, and skin. These nonoverlapping tissue-specific patterns are identical to those previously observed for mouse ADH1 and ADH4, thus providing further evidence that Xenopus ADH1 and ADH4 are orthologs of mouse ADH1 and ADH4, respectively. During Xenopus embryonic development ADH1 mRNA was first detectable by Northern blot analysis at stage 35, whereas ADH4 mRNA was undetectable through stage 47. Whole-mount in situ hybridization indicated that ADH1 expression was first localized in the pronephros during Xenopus embryogenesis, thus conserved with mouse embryonic ADH1 which is first expressed in the mesonephros. ADH4 expression was not detected in Xenopus embryos by whole-mount in situ hybridization but was localized to the gastric mucosa of the adult stomach, a property shared by mouse ADH4. Conserved expression of ADH1 and ADH4 in retinoid-responsive epithelial tissues of amphibians and mammals argue that these enzymes may perform essential retinoid signaling functions during development of the pronephros, mesonephros, liver, and lower digestive tract in the case of ADH1 and in the skin and upper digestive tract in the case of ADH4.

Alcohol Dehydrogenase↗
PubMed1998

The cdc25B phosphatase is essential for the G2/M phase transition in human cells.

Cdc25 phosphatases play key roles in cell cycle progression by activating cyclin-dependent kinases. In human cells, cdc25 proteins are encoded by a multigene family, consisting of cdc25A, cdc25B and cdc25C. While cdc25A plays a crucial role at the G1/S phase transition, cdc25C is involved in the dephosphorylation and activation of the mitotic kinase, cdc2/cyclinB. In addition, cdc25C itself is regulated by cdc2/cyclinB which then creates a positive feedback loop that controls entry into mitosis. In this study we show that the activity of cdc25B appears during late S phase and peaks during G2 phase. Both in vitro and in vivo cdc25B is activated through phosphorylation during S-phase. Using a cell duplication, microinjection assay we show that ablation of cdc25B function by specific antibodies blocks cell cycle progression in Hs68 cells by inhibition of entry into mitosis. Cdc25B function neither plays a role in later stages of mitosis nor for the inititation of DNA replication. These results indicate that cdc25B is a mitotic regulator that might act as a 'starter phosphatase' to initiate the positive feedback loop at the entry into M phase.

Antibodies↗