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PubMed1999

Micrometastases in bone marrow: prognostic indicators for pancreatic cancer.

Minimal residual disease in patients with operable pancreatic carcinoma is frequently missed by current noninvasive tumour staging. We applied an immunocytochemical cytokeratin assay that allows identification of individual pancreatic carcinoma cells disseminated to bone marrow. Prior to therapy, bone marrow was aspirated from the upper iliac crest of 48 patients with ductal adenocarcinoma of the pancreas at various disease stages and an age-matched control group of 33 noncarcinoma patients. Tumor cells in cytologic bone marrow preparations were detected with monoclonal antibodies (mAbs) CK2, KL1, and A45-B/B3 to epithelial cytokeratins (CK) using the alkaline phosphatase antialkaline phosphatase method. CK-positive cells were found in 14 (48.4%) of 31 cancer patients treated with curative intent and in 10 (58.8%) of 18 patients with extended disease. The overall frequency of these cells was 1 to 83 per 5x10(5) mononuclear cells with no significant differences between patients at different tumor stages and lymph node involvement. After a median follow-up of 22.8 months (range 3-48 months), 6 (40.0%) of 15 patients who underwent complete surgical resection but had tumor cells in bone marrow presented with distant metastasis and 7 (46.7%) had local relapse compared to none of 12 corresponding patients without such cells (p<0.05). Univariate survival analyses revealed that the presence of CK-positive cells was predictive of reduced overall survival. In conclusion, anticytokeratin mAbs are reliable probes for the immunocytochemical detection of single pancreatic cancer cells disseminated to bone marrow. Thus the described technique may help identify patients with pancreatic cancer and at potentially high risk of early metastatic relapse. The results promise to be of important assistance for determining prognosis and the consequences in therapy of early stage pancreatic cancer.

Adenocarcinoma↗
PubMed2004

Molecular characterization of the porcine testis-specific phosphoglycerate kinase 2 (PGK2) gene and its association with male fertility.

We have isolated and characterized the porcine testis-specific phosphoglycerate kinase 2 (PGK2) gene, and 1665 bp of full-length PGK2 cDNA were also compiled using modified rapid amplification 5'-RACE and 3'-RACE information. The results of genomic and cDNA sequences of the porcine PGK2 gene demonstrated that it is a single-exon intronless gene with a complete open reading frame of 1251 bp encoding a PGK protein of 417 amino acids. Real-time quantitative PCR results showed that PGK2 mRNA was solely expressed in the testis. There was a lower amount of PGK2 expression in the testis of a 10-month-old herniated boar and a very small amount of PGK2 expression in the testis of an 8-week-old cryptorchid piglet compared to an adult boar. Two SNPs in the PGK2 gene (SNP-A: T427C; SNP-B: C914A) resulting in amino acid substitutions (SNP-A: Ser102-Pro102; SNP-B: Thr264-Lys264) were detected and genotyped among six pig breeds. The nucleotide C at SNP-A responsible for the amino acid exchange to proline could lead to the loss of a casein kinase II (CK2) phosphorylation site in the PGK2 peptide. Association analyses between PGK2 genotypes and several traits of sperm quantity and quality were performed. The results showed that SNP-B has a positive significant effect on semen volume in the breed Pietrain (p = 0.08), i.e., boars carrying genotype CC revealed an increased volume of 49 ml compared with boars having the genotype AA.

Amino Acid Sequence↗
PubMed2006

Lysine catabolism, an effective versatile regulator of lysine level in plants.

Lysine is a nutritionally important essential amino acid, whose synthesis in plants is strongly regulated by the rate of its synthesis. Yet, lysine level in plants is also finely controlled by a super-regulated catabolic pathway that catabolizes lysine into glutamate and acetyl Co-A. The first two enzymes of lysine catabolism are synthesized from a single LKR/SDH gene. Expression of this gene is subject to compound developmental, hormonal and stress-associated regulation. Moreover, the LKR/SDH gene of different plant species encodes up to three distinct polypeptides: (i) a bifunctional enzyme containing the linked lysine-ketoglutarate (LKR) and saccharopine dehydrogenase (SDH) whose LKR activity is regulated by its linked SDH enzyme; (ii) a monofunctional SDH encoded by an internal promoter, which is a part of the coding DNA region of the LKR/SDH gene; and (iii) a monofunctional, highly potent LKR that is formed by polyadenylation within an intron. LKR activity in the bifunctional LKR/SDH polypeptide is also post-translationally regulated by phosphorylation by casein kinase-2 (CK2), but the consequence of this regulation is still unknown. Why is lysine metabolism super-regulated by synthesis and catabolism? A hypothesis addressing this important question is presented, suggesting that lysine may serve as a regulator of plant growth and interaction with the environment.

Animals↗
PubMed2005

Isolation and functional characterisation of two new bZIP maize regulators of the ABA responsive gene rab28.

The plant hormone abscisic acid regulates gene expression in response to growth stimuli and abiotic stress. Previous studies have implicated members of the bZIP family of transcription factors as mediators of abscisic acid dependent gene expression through the ABRE cis-element. Here, we identify two new maize bZIP transcription factors, EmBP-2 and ZmBZ-1 related to EmBP-1 and OsBZ-8 families. They are differentially expressed during embryo development; EmBP-2 is constitutive, whereas ZmBZ-1 is abscisic acid-inducible and accumulates during late embryogenesis. Both factors are nuclear proteins that bind to ABREs and activate transcription of the abscisic acid-inducible gene rab28 from maize. EmBP-2 and ZmBZ-1 are phosphorylated by protein kinase CK2 and phosphorylation alters their DNA binding properties. Our data suggest that EmBP-2 and ZmBZ-1 are involved in the expression of abscisic acid inducible genes such as rab28 and their activity is modulated by ABA and by phosphorylation.

Abscisic Acid↗
PubMed1991

Establishment and characterization of hybrid rat mast cells.

Rat peritoneal mast cells (RPMC) and rat basophilic leukemia (RBL) cells are representative of connective tissue-type (CTMC) and mucosal-type (MMC) mast cells, respectively. Using polyethylene glycol, we have fused RPMC with 6-thioguanine resistant, HAT (hypoxanthine, aminopterin, thymidine) sensitive RBL-CA10.7 or RBL-CK2 cells, yielding several hybrid rat mast cell lines (HRMC). The hybridomas exhibited different size and cytoplasmic granularity when compared with parental cell lines. Analysis of both high (Fc epsilon RI) and low affinity (Fc epsilon RL) receptors for IgE revealed that the hybrid lines had more variable receptor patterns than the parent lines. Three hybridoma lines were chosen for further study. Differential histochemical staining with alcian blue and safranin O dyes indicated the hybrids to be predominantly of the MMC type: however, a few cells of one of these uncloned hybridomas were found to be of the CTMC type. Attempts to isolate the CTMC hybridomas yielded one culture which was predominantly of the CTMC phenotype and in a number of other cultures, cells were found expressing simultaneously both the CTMC and the MMC phenotype. After 3 weeks in culture, however, all hybridomas, including those which were cloned further, expressed only the MMC histochemical phenotype. This was found to correlate with the presence of rat mast cell protease II (RMCPII) and the absence of RMCPI in all hybridomas, as detected by Western blot analysis. In addition, the histamine content of all cells was significantly lower than that of the parent RPMC. Most hybrid mast cells expressed both Fc epsilon RI and Fc epsilon RL which in some cases exhibited significant variations in the Mr. These results indicate that somatic cell hybrids expressing the MMC and CTMC phenotype can be produced by the fusion of RBL and RPMC. The CTMC phenotype, however, is unstable, and possible reasons for this are discussed.

Animals↗
PubMed1985

Creatine kinase (CK)-linked IgA in Isaacs' syndrome. An immune complex disease?

Electrophoresis of serum from a patient with Isaacs' syndrome revealed an atypical creatine kinase (CK) isoenzyme pattern which contained an extra band migrating between CK2(MB) and CK3(MM). Immunofixation demonstrated that the extra band was a complex of CK3(MM) and IgA. The presence of this complex seemed to correlate with increased serum CK levels which were associated with the aggravation of symptoms. Immunofluorescence studies on muscle biopsy samples revealed the presence of the complex in the muscle fiber membrane and motor endplate. The existence of CK-linked IgA in an Isaacs' syndrome suggests that an immunological abnormality may play a role in the pathological process of this rare syndrome.

Chemical Phenomena↗
PubMed1995

Creatine kinase isoenzyme profiles in the plasma of the domestic fowl (Gallus domesticus): effects of acute heat stress.

Creatine kinase isoenzyme activities in extracts of plasma, skeletal muscle, heart and brain tissue of domestic fowls were separated by anion exchange chromatography and tissue specific distributions of the isoenzyme designated MM-CK, BB-CK1 and BB-CK2 were demonstrated. The muscle isoenzyme (MM-CK) was the predominant form in plasma (99 per cent) and its activity increased in response to an episode of acute heat stress.

Acute Disease↗
PubMed1995

Immunocytochemical detection of isolated tumour cells in bone marrow of patients with untreated stage C prostatic cancer.

The micrometastatic spread of tumour cells is usually missed by conventional diagnostic techniques, although this spread largely determines the prognosis of patients with primary epithelial cancers. By use of the monoclonal antibody, CK2, to epithelial cytokeratin component number 18 (CK18), individual disseminated carcinoma cells present in bone marrow of cancer patients can now be identified. In the present study, this approach has been applied to patients with virginal stage C adenocarcinoma of the prostate. Double-sided aspirates of iliac bone marrow from 24 of 44 evaluable patients (54.4%) exhibited between one and 38 CK18-positive cells per sample of 2 x 10(6) mononuclear cells. In 13 of these 24 positive patients, CK-positive cells were only detected in one of the two aspirates analysed. There was no statistically significant correlation between this finding and established risk factors, such as the volume and histological grade of the primary tumour or the concentration of prostate specific antigen and prostatic acid phosphatase in serum. The follow-up time is too short to provide meaningful data on the prognostic significance of isolated CK18-positive cells in bone marrow, which, however, has been recently demonstrated in other types of primary epithelial cancers. In conclusion, the presence of prostatic tumour cells in bone marrow might be interpreted as an indicator of the metastatic capacity of an individual primary tumour. The immunocytochemical detection of these cells may, therefore, be useful for increasing the precision of current tumour staging, and to monitor minimal residual cancer in an individual patient.

Adenocarcinoma↗
PubMed1996

Expression of MHC molecules and ICAM-1 on non-small cell lung carcinomas: association with early lymphatic spread of tumour cells.

Early microdissemination of tumour cells determines the prognosis of patients with apparently localised non-small cell lung cancer (NSCLC). Monoclonal antibodies to epithelial antigens can now be used to detect single carcinoma cells present in mesenchymal secondary organs such as bone marrow or lymph nodes. The present study was designed to obtain insights into the potential role of the immune system in lymphatic and haematogenous microdissemination of NSCLC cells. Using immunohistochemical staining of primary NSCLC, we assessed the expression pattern of molecules mediating an efficient cellular immune response, that is, MHC class I and class II antigens and the intercellular adhesion molecule-1 (ICAM-1). All 58 patients evaluated were staged as free of overt metastases by conventional clinico-pathological screening. Isolated tumour cells in bone marrow or lymph nodes were identified with mAb CK2 to cytokeratin component No. 18 and mAb BerEp-4 to glycoproteins of 34 and 39 kd present on epithelial cells, respectively. MHC class I expression on primary tumours was reduced or absent in 6/10 (60.0%) patients with isolated cancer cells in lymph nodes as compared to 6/33 tumours (18.1%) without such tumour cell dissemination (P = 0.01). MHC class II molecules on primary tumours were detected in 1/10 (10.0%) patients with micrometastases to regional lymph nodes and in 10/33 (30.3%) patients without such a tumour cell spread. None of the 10 patients with nodal microdissemination expressed ICAM-1 on their primary NSCLC, while such expression was detectable in 12/33 (36.4%) patients without this dissemination (P = 0.01). In contrast, the detection of tumour cells in bone marrow was not correlated to the expression of any of these immunoregulatory molecules. Our data suggest that escape caused by deficient expression of MHC class I antigens and ICAM-1 on tumour cells may support homing or survival of disseminated tumour cells in lymphoid tissue.

Adult↗
PubMed1996

Epithelial tumour cells in bone marrow of patients with pancreatic carcinoma detected by immunocytochemical staining.

In the present study, epithelial cells in the bone marrow of 42 patients with pancreatic carcinoma were identified immunocytochemically with monoclonal antibodies (MAbs) CK2, KL1 and A45-B/B3 directed to epithelial cytokeratins (CK), using the alkaline phosphatase anti-alkaline phosphatase method. The specificity of the MAbs was demonstrated by negative staining of marrow from 25 non-carcinoma age-matched control patients. Analysis of bone marrow aspirates from cancer patients revealed CK-positive cells in 14 (58.3%) of 24 cancer patients treated with curative intent and 10 (55.6%) of 18 patients with extended disease. After a median follow-up of 15.6 months (range 3-31 months), 5 (35.7%) out of 14 patients who underwent complete surgical resection but had tumour cells in bone marrow presented with distant metastasis and 6 (42.9%) with local relapse as compared to none of 10 corresponding patients without such cells (P < 0.05). The described technique may help to identify patients with pancreatic cancer and potential high risk of early metastatic relapse. The results promise to be of important assistance in determining prognosis and consequences in therapy of early stage pancreatic cancer.

Adenocarcinoma↗
PubMed2004

The cytoplasmic tail of the cation-independent mannose 6-phosphate receptor contains four binding sites for AP-1.

The trafficking of the cation-independent mannose 6-phosphate receptor between the trans-Golgi network and endosomes requires binding of sorting determinants in the cytoplasmic tail of the receptor to adaptor protein complex-1 (AP-1). Using a GST pull-down binding assay, four binding motifs were identified in the cytoplasmic tail: a tyrosine-based motif ((26)YSKV(29)), an internal dileucine-based motif ((39)ETEWLM(44)), and two casein kinase 2 sites ((84)DSEDE(88) and (154)DDSDED(159)). The YSKV motif mediated the strongest interaction with AP-1 and the two CK2 motifs bound AP-1 only when they were phosphorylated. The COOH-terminal dileucines were not required for interaction with AP-1.

Adaptor Protein Complex 1↗
PubMed2005

Purification and biochemical characterization of a fibroblast growth factor-binding protein (FGF-BP) from the lactoferrin fraction of bovine milk.

By means of gel filtration on a TSK-gel HPLC column in the presence of 8 M urea, a 37-kDa polypeptide (p37) was completely separated from lactoferrin (LF) in the heparin HII fraction of the partially purified LF fraction prepared from bovine milk. Purified p37 was identified as a fibroblast growth factor-binding protein (FGF-BP), since its N-terminal 14 amino acid residues (KKEGRNRRGSKASA) were 100% identical to the corresponding sequence of bovine FGF-BP. It was found, in vitro, that (i) p37 had a higher binding affinity with bFGF than bLF; (ii) p37 functioned as a phosphate acceptor for at least three protein kinases (PKA, CK1 and CK2); (iii) bLF stimulated about 3-fold the PKA-mediated phosphorylation of p37, but suppressed its phosphorylation by CK1; and (iv) galloyl pedunculagin was an effective inhibitor for the phosphorylation of p37 by PKA and CK1. Furthermore, the physiological correlation between p37 and bLF may be regulated through specific phosphorylation of p37 by PKA, since p37 fully phosphorylated by PKA did not bind to bLF in vitro. The sulfatide-induced conformational changes in p37 enabled the phosphorylation of p37 by CK1 and also reduced its ability to bind with bLF in vitro. From these results presented here, it is concluded that (i) p37 (FGF-BP) may be tightly associated with bLF in bovine milk; and (ii) the physiological correlation between p37 and bLF may be regulated by the PKA-mediated full phosphorylation of p37 or by the direct binding of sulfatide to p37 in vivo.

Amino Acid Sequence↗
PubMed2004

Molecular cloning, sequence analysis, and expression of a cDNA encoding the luciferase from the glow-worm, Lampyris turkestanicus.

The first cDNA from lampyridae encoding a glow-worm luciferase from lantern mRNA of Lampyris turkestanicus has been cloned, sequenced, the amino acid sequence predicted, and the sequence reported to GenBank. The cDNA was 1644 base pairs in length and coding a 547-residue protein. The deduced amino acid sequence of the luciferase gene of L. turkestanicus showed 98.7% and 95.8% identity to Lampyris noctiluca and Pyrocoelia rufa, respectively. Phylogenetic analysis further confirmed that the deduced amino acid sequences of L. turkestanicus luciferase gene belong to the same subfamily, Lampyrinae. The cDNA encoding the luciferase of L. turkestanicus was expressed as a 62kDa band in recombinant Escherichia coli and showed green luminescence in the presence of luciferin. Amongst amino acid differences of L. turkestanicus and L. noctiluca (its clade) there are two important substitutions. Signature amino-acid sequences and motifs found in the deduced sequence are CK2-phospho site, ASN-glycosylation, myristoylation site, PKC-phospho site, microbodies C-terminal targeting signal, and AMP-binding domain.

Amino Acid Sequence↗
PubMed2005

The N-terminus of Drosophila ESC mediates its phosphorylation and dimerization.

The ESC protein, like other Polycomb Group proteins, is required for heritable silencing of the homeotic genes. ESC is phosphorylated in vivo, but the region of ESC that is phosphorylated and its consequences are not known. Here, we show that the amino-terminal region of ESC (residues 1-60) mediates its phosphorylation and dimerization. Phosphorylation of ESC1-60 in vitro by CK1 and CK2 strongly enhances its dimerization. Both phosphorylation and dimerization are conserved in the mammalian ESC homolog EED, suggesting that they play important roles in vivo. One role is suggested by the effect of phosphatase treatment on native ESC complexes, which does not affect the integrity of the 600 kDa ESC/E(Z) complex, but eliminates the 1 MDa ESC/E(Z) complex, which is distinguished from the former by the presence of the additional subunits PCL and RPD3. Thus, stability and perhaps assembly of larger ESC complexes may depend on ESC phosphorylation.

Amino Acid Sequence↗
PubMed2006

Selective downregulation of EGF receptor and downstream MAPK pathway in human cancer cell lines by active components partially purified from the seeds of Livistona chinensis R. Brown.

Deregulation of protein kinase-mediated signaling events is one of the major causes to malignant transformation. In this work, we tried to purify protein kinase inhibitory activity and antitumor activity from ethanol extracts of the seeds of Livistona chinensis R. Brown (LC), a traditional herb used for the treatment of nasopharyngeal carcinoma (NPC). Both activities were found to be co-purified in various chromatography steps, and a highly purified fraction, LC-X, was obtained and its biological effects were characterized further. LC-X inhibited the activities of various protein kinases in vitro, including PAK2, PKA, PKC, GSK-3alpha, CK2, mitogen-activated protein kinase (MAPK), and JNK1, with IC(50) between approximately 1 and 40microg/ml. The proliferation of two NPC (NPC-TW02 and -TW04) and one breast cancer (MCF-7) cell lines, but not the epidermoid (A431) and cervical (HeLa) carcinoma cell lines, were significantly blocked by LC-X at the dose of >50microg/ml. Cell cycle arrested at G(2)/M phase and apoptosis were detected in NPC-TW02 cells treated with LC-X for 24h. Further studies revealed that epidermal growth factor (EGF)-induced activation of epidermal growth factor receptor (EGFR) and MAPK could be potently inhibited by LC-X in both NPC-TW02 and A431cells in a dose-dependent manner. More interestingly, the level of EGFR protein detected by Western blot decreased drastically in LC-X-treated A431 and NPC-TW02 cells in a dose- and time-dependent fashion. Further analysis of the plasma membrane and cytosolic fractions from LC-X-treated and untreated A431 cells showed that a 170kDa protein selectively disappeared from the plasma membrane of LC-X-treated cells. The protein was identified as EGFR by MALDI-TOF mass spectrometry, indicating EGFR as a selective target for LC-X. Moreover, the electrophoretic mobility of purified EGFR in SDS-PAGE was altered dramatically post LC-X treatment, suggesting that LC-X may chemically modify EGFR. In conclusion, the active components with both antitumor and protein kinases inhibitor activities were highly purified from LC, which can inhibit the EGF signaling events mainly through EGFR modification. Blockage of the functions of EGFR may account for the antitumor activity of these active components.

Antineoplastic Agents↗
PubMed2004

Defective glycosylation of calsequestrin in heart failure.

OBJECTIVE: Levels of Ca2+ regulatory proteins have been extensively analyzed in cardiomyopathies as possible indices of change in sarcoplasmic reticulum (SR) structure and function. Measures of calsequestrin (CSQ), however, a critical protein component of the Ca2+ release complex in junctional sarcoplasmic reticulum, have provided little or no evidence of underlying dysfunction. We previously reported that calsequestrin isolated from heart tissue exists in a variety of glycoforms and phosphoforms reflecting mannose trimming of N-linked glycans and phosphorylation and dephosphorylation on protein kinase CK2-sensitive sites. METHODS: Here, we tested whether the distribution of molecular forms changes in heart failure (HF) reflecting possible remodeling of diseased tissue. Canine hearts were paced (220 beats/min) for 6-8 weeks to induce heart failure. Calsequestrin was purified from heart failure and sham-operated (control) treated canine ventricles and analyzed by electrospray mass spectrometry. RESULTS: The results showed striking changes in the mass distribution of calsequestrin molecules present in tissue from heart failure (five animals) compared with control (five animals). In heart failure, calsequestrin contained glycan structures that were uncharacteristic of normal junctional sarcoplasmic reticulum, consistent with altered metabolism or altered trafficking through secretory compartments. Glycoforms containing Man8,9, expected for a phenotype less muscle-like, were more than doubled in heart failure hearts, and molecules were also phosphorylated to a higher level. CONCLUSIONS: These data reveal in tachycardia-induced heart failure a new and potentially important change in the mannose content of calsequestrin glycans, perhaps indicative of defective junctional SR trafficking and Ca2+ release complex assembly.

Animals↗
PubMed2005

The casein kinase 1 family: participation in multiple cellular processes in eukaryotes.

Phosphorylation of serine, threonine and tyrosine residues by cellular protein kinases plays an important role in the regulation of various cellular processes. The serine/threonine specific casein kinase 1 and 2 protein kinase families--(CK1 and CK2)--were among the first protein kinases that had been described. In recent years our knowledge of the regulation and function of mammalian CK1 kinase family members has rapidly increased. Extracellular stimuli, the subcellular localization of CK1 isoforms, their interaction with various cellular structures and proteins, as well as autophosphorylation and proteolytic cleavage of their C-terminal regulatory domains influence CK1 kinase activity. Mammalian CK1 isoforms phosphorylate many different substrates among them key regulatory proteins involved in the control of cell differentiation, proliferation, chromosome segregation and circadian rhythms. Deregulation and/or the incidence of mutations in the coding sequence of CK1 isoforms have been linked to neurodegenerative diseases and cancer. This review will summarize our current knowledge about the function and regulation of mammalian CK1 isoforms.

Amino Acid Sequence↗
PubMed2006

The PH domain containing protein CKIP-1 binds to IFP35 and Nmi and is involved in cytokine signaling.

The pleckstrin homology domain-containing protein CKIP-1 is implicated in regulation of cell differentiation, apoptosis, cytoskeleton as well as recruitment of CK2 and ATM kinases to plasma membrane. Protein-protein interactions of CKIP-1 were required for these functions. Here we identify the IFN-induced protein IFP35 and its homologue Nmi as two novel CKIP-1 interacting partners. The NID domains of IFP35 and Nmi are required for the interactions. Similar to IFP35 and Nmi, CKIP-1 can be up-regulated dramatically by IFN-gamma and IL-2 and form homodimer and homotrimer in vivo. Nmi stabilizes IFP35, whereas CKIP-1 destabilizes IFP35 via inhibiting IFP35-Nmi interaction. The ratio of Nmi to CKIP-1 determines the stability of IFP35 and control cytokine signaling in a novel mechanism. Importantly, similar to Nmi and contrast to IFP35, CKIP-1 inhibits tumor cell growth and Akt-mediated cell survival. Thus, our results provide a novel role of CKIP-1 in cytokine signaling response and the biochemical mechanism, by which two previously identified modulators IFP35 and Nmi are involved via interactions.

Animals↗