Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HSP27 form oligomeric structures up to 800 Kda. In cultured cells, the equilibrium between small and large oligomers shifted towards smaller oligomers when phosphorylated on serine residues. To further explore HSP27 structural organization and its repercussion in HSP27 antiapoptotic and tumorigenic properties, we transfected colon cancer REG cells with wild type HSP27 and two mutants in which the phosphorylatable serine residues have been replaced by alanine (to mimic the non phosphorylated protein) or aspartate (to mimic the phosphorylated protein). In growing cells, wild type and alanine mutant formed small and large oligomers and demonstrated antiapoptotic activity while aspartate mutant only formed small multimers and had no antiapoptotic activity. In a cell-free system, only large oligomeric structures interfered with cytochrome c-induced caspase activation, thereby inhibiting apoptosis. The inability of the aspartate mutant to form large oligomers and to protect tumor cells from apoptosis was overcome by growing the cells in vivo, either in syngeneic animals or nude mice. These observations were reproduced by culturing the cells at confluence in vitro. In conclusion (1) large oligomers are the structural organization of HSP27 required for its antiapoptotic activity and (2) cell-cell contacts induce the formation of large oligomers, whatever the status of phosphorylatable serines, thereby increasing cell tumorigenicity.
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PMID:Differential regulation of HSP27 oligomerization in tumor cells grown in vitro and in vivo. 1103 3

Trypsinogen is a serine proteinase produced mainly by the pancreas, but it has recently been found to be expressed also in several cancers such as ovarian and colon cancer and in vascular endothelial cells. In this study, we found that trypsinogen-1 and -2 are present at high concentrations (median levels, 0.4 and 0.5 mg/L, respectively) in human seminal fluid and purified them to homogeneity by immunoaffinity and anion exchange chromatography. Purified trypsinogen isoenzymes displayed a M(r) of 25 to 28 kd in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. Most of the trypsinogen-1 purified from seminal fluid was enzymatically active whereas trypsinogen-2 occurred as the proform, which could be activated by enteropeptidase in vitro. Immunohistochemically, trypsinogen protein was detected in the human prostate, urethra, utriculus, ejaculatory duct, seminal vesicles, deferent duct, epididymal glands, and testis. Expression of trypsinogen mRNA in the same organs was demonstrated by in situ hybridization. Trypsinogen mRNA was also detected in the prostate and seminal vesicles by reverse transcriptase-polymerase chain reaction and Northern blotting. Isolated trypsin was shown to activate the proenzyme form of prostate-specific antigen. These results suggest that trypsinogen isoenzymes found in seminal fluid are produced locally in the male genital tract and that they may play a physiological role in the semen.
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PMID:Expression and characterization of trypsinogen produced in the human male genital tract. 1110 74

In response to DNA damage, p53 protein transiently stabilizes and accumulates in the nucleus, where it performs its role as a transcription factor. Phosphorylation of p53 increases its sequence-specific DNA-binding activity. In the present study, we have examined the effect of methylmethane sulfonate (MMS) to HCT-116 human colon cancer cells on the phosphorylation of p53. Results show that p53 protein becomes phosphorylated at serine 15 (Ser15) and Ser392 residues after treatment with MMS in a time-dependent manner. Increased levels of phospho-p53(Ser15) and phospho-p53(Ser392) were maintained up to 50 h of the MMS treatment. We also examined the involvement of probable kinase(s), which could be responsible for MMS-induced phosphorylation of p53 at Ser15 and Ser392. In vitro phosphorylation assay, carried out with the immunoprecipates of MMS-treated cells, showed an increased phosphorylation of p53 by c-Jun kinase 1 (JNK1) at early time points (2.5 h). However, with cyclin-dependent kinase (Cdk2) and TFIIH complex associated kinase CAK, the phosphorylation of p53 was increased at later time points (25 h). The phosphorylation of p53 by Cdc2 and MAPK (p38) kinases remained unaffected in the MMS-treated versus untreated cells. The MMS-induced phosphorylation of p53 correlates with our previous findings of p53's ability for increased sequence-specific DNA-binding and transcriptional activity in the cells treated with DNA alkylating agents.
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PMID:DNA alkylation-induced phosphorylation of p53 and activation of kinases in colon cancer cells. 1149 44

The protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is cleaved and activated by trypsin. We investigated the expression of PAR-2 and the role of trypsin in cell proliferation in human colon cancer cell lines. A total of 10 cell lines were tested for expression of PAR-2 mRNA by Northern blot and RT-PCR. PAR-2 protein was detected by immunofluorescence. Trypsin and the peptide agonist SLIGKV (AP2) were tested for their ability to induce calcium mobilization and to promote cell proliferation on serum-deprived cells. PAR-2 mRNA was detected by Northern blot analysis in 6 out of 10 cell lines [HT-29, Cl.19A, Caco-2, SW480, HCT-8 and T84]. Other cell lines expressed low levels of transcripts, which were detected only by RT-PCR. Further results were obtained with HT-29 cells: (1) PAR-2 protein is expressed at the cell surface; (2) an increase in intracellular calcium concentration was observed upon trypsin (1-100 nM) or AP2 (10-100 microM) challenges; (3) cells grown in serum-deprived media supplemented with trypsin (0.1-1 nM) or AP2 (1-300 microM) exhibited important mitogenic responses (3-fold increase of cell number). Proliferative effects of trypsin or AP2 were also observed in other cell lines expressing PAR-2. These data show that subnanomolar concentrations of trypsin, acting at PAR-2, promoted the proliferation of human colon cancer cells. The results of this study indicate that trypsin could be considered as a growth factor and unravel a new mechanism whereby serine proteases control colon tumours.
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PMID:Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2. 1153 Dec 66

p21-activated protein kinase (PAK) serine/threonine kinases are important effectors of Rho family GTPases and have been implicated in the regulation of cell morphology and motility, as well as in cell transformation. To further investigate the possible involvement of PAK kinases in tumorigenesis, we analyzed the expression of several family members in tumor cell lines. Here we demonstrate that PAK4 is frequently overexpressed in human tumor cell lines of various tissue origins. We also have identified serine (Ser-474) as the likely autophosphorylation site in the kinase domain of PAK4 in vivo. Mutation of this serine to glutamic acid (S474E) results in constitutive activation of the kinase. Phosphospecific antibodies directed against serine 474 detect activated PAK4 on the Golgi membrane when PAK4 is co-expressed with activated Cdc42. Furthermore, expression of the active PAK4 (S474E) mutant has transforming potential, leading to anchorage-independent growth of NIH3T3 cells. A kinase-inactive PAK4 (K350A,K351A), on the other hand, efficiently blocks transformation by activated Ras and inhibits anchorage-independent growth of HCT116 colon cancer cells. Taken together, our data strongly implicate PAK4 in oncogenic transformation and suggest that PAK4 activity is required for Ras-driven, anchorage-independent growth.
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PMID:Requirement for PAK4 in the anchorage-independent growth of human cancer cell lines. 1166 77

The CHK2 gene encodes a protein kinase that is important for the regulation of cell cycle arrest after DNA damage. CHK2 acts downstream of ataxia teleangiecstasia mutated (ATM), modulates the function of p53 and may help mediate cell cycle arrest at G2/M by phosphorylation of Cdc25C. Recently, the human homolog of the checkpoint kinase Cds1 (CHK2) has been suggested to be a tumor suppressor gene. Heterozygous germline mutations have been reported in Li-Fraumeni syndrome (LFS), a highly penetrant familial cancer phenotype, and in sporadic colon cancer. LFS is associated with the development of lymphoid malignancies, especially childhood ALL. Therefore, we analyzed the DNA from 143 lymphoid malignancies to determine whether they had mutations of the CHK2 gene. The 14 exons of CHK2 were studied by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and sequencing of aberrantly migrating bands. One missense mutation changing serine to phenylalanine (codon 428) in an evolutionarily highly conserved domain was found in a non-Hodgkin's aggressive lymphoma. Another point mutation in the non-coding region was identified in one of adult T-cell leukemias (ATL) samples. This result suggests that mutation of the CHK2 gene may rarely be involved in the development of selected lymphomas.
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PMID:Analysis of the CHK2 gene in lymphoid malignancies. 1169 18

Membrane mucins have several functions in epithelial cells including cytoprotection, extravasation during metastases, maintenance of luminal structure, and signal transduction. In this paper we describe a large membrane mucin expressed in the normal intestine. This novel mucin, designated MUC17, contains an extended, repetitive extracellular glycosylation domain and a carboxyl terminus with two EGF-like domains, a SEA module domain, a transmembrane domain, and a cytoplasmic domain with potential serine and tyrosine phosphorylation sites. RNA blot analysis and in situ hybridization indicates that MUC17 is expressed in select pancreatic and colon cancer cell lines and in intestinal absorptive cells. Radiation hybrid mapping localized MUC17 to chromosome 7q22 where it resides in close proximity with three other membrane mucin genes, MUC3A, MUC3B, and MUC12. Thus, these membrane mucins reside together in a gene cluster, but are expressed in different tissues and are likely to have different functions as well.
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PMID:MUC17, a novel membrane-tethered mucin. 1185 12

p53 is an important player in the cellular response to genotoxic stress whose functions are regulated by phosphorylation of a number of serine and threonine residues. Phosphorylation of p53 influences its DNA-binding and gene regulation activities. This study examines p53 phosphorylation in HCT-116 (MMR-deficient) and HCT-116+ch3 (MMR-proficient) human colon cancer cells treated with a S(N)2 DNA-alkylating agent, methylmethane sulfonate (MMS). MMS induces phosphorylation of p53 on Ser15 and Ser392 in a dose- and time-dependent manner. MMS-induced p53 phosphorylation is independent of DNA mismatch repair (MMR) activity. Nuclear extracts from MMS-treated HCT-116 cells had higher p21WAF1/Cip1 (p21) promoter DNA-binding activity in vitro opposed to untreated cells. After MMS treatment, the activation of the cloned p21 promoter in a transient transfection assay and endogenous p21 mRNA levels in HCT-116(p53+/+) versus HCT-116(p53-/-) cells increased, which correlates with an increased levels of phospho-p53(Ser15) and phospho-p53(Ser392). These results suggest that SN2 DNA-alkylating agent-induced phosphorylation of p53 on Ser15 and Ser392 increases its DNA-binding properties to cause an increased expression of p21 that may play a role in cell cycle arrest and/or apoptosis of HCT-116 cells.
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PMID:SN2 DNA-alkylating agent-induced phosphorylation of p53 and activation of p21 gene expression. 1189 Sep 31

K-ras mutation is the most common oncogenic alteration in various human cancers including colorectal carcinomas. Point mutations have the potential to activate the K-ras gene if they occur in the critical coding sequences. Almost all of these mutations have been localized in codons 12, 13 and 61. We report a case of colon cancer presenting point mutations at both codons 12 and 22 of the K-ras gene. PCR-SSCP and subsequent sequencing revealed that GGT (glycine, wild-type) to AGT (serine) substitution at codon 12 and CAG (glutamine, wild-type) to CGG (arginine) substitution at codon 22 occurred in the same allele.
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PMID:Concurrent mutations of K-ras oncogene at codons 12 and 22 in colon cancer. 1211 Jun 40

Protein kinase C (PKC), a family of serine-threonine kinases, has been implicated in the regulation of colon tumorigenesis. However, the specific isoform of PKC involved in this process is not clear. In the present study, we found that treatment of the cultured human colon cancer cell line COLO-205 with a PKC agonist, 12-O-tetradecanoylphorbol-13-acetate (TPA), resulted in cell-cycle arrest at the G(0)/G(1) phase, decrease in cell number, PKCgamma isoform translocation, and upregulation of p21(Cip1) protein. Pretreatment of the cells with a PKC inhibitor, staurosporine, prevented the TPA-induced upregulation of p21(Cip1) protein. Based on the findings of the present study including that (a) both extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) were activated in the TPA-treated COLO-205 cells, (b) pretreatment with the mitogen-activated protein kinase kinase inhibitor PD98059 but not with the p38 mitogen-activated protein kinase inhibitor SB203580 blocked the TPA-induced p21(Cip1) in COLO-205 cells, and (c) transient transfection of the COLO-205 cells with dominant negative ERK or JNK plasmid significantly suppressed the TPA-induced p21(Cip1) protein induction, we conclude that both the ERK and JNK pathways are involved in the TPA-induced upregulation of p21(Cip1) protein in the COLO-205 cells.
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PMID:Involvement of both extracellular signal-regulated kinase and c-jun N-terminal kinase pathways in the 12-O-tetradecanoylphorbol-13-acetate-induced upregulation of p21(Cip1) in colon cancer cells. 1220 64


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