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PubMed1999

NH2- and COOH-terminal truncations of murine granulocyte chemotactic protein-2 augment the in vitro and in vivo neutrophil chemotactic potency.

Chemokines are important mediators of leukocyte migration during the inflammatory response. Post-translational modifications affect the biological potency of chemokines. In addition to previously identified NH2-terminally truncated forms, COOH-terminally truncated forms of the CXC chemokine murine granulocyte chemotactic protein-2 (GCP-2) were purified from conditioned medium of stimulated fibroblasts. The truncations generated 28 natural murine GCP-2 isoforms containing 69-92 residues, including most intermediate forms. Both NH2- and COOH-terminal truncations of GCP-2 resulted in enhanced chemotactic potency for human and murine neutrophils in vitro. The truncated isoform GCP-2(9-78) was 30-fold more potent than intact GCP-2(1-92)/LPS-induced CXC chemokine (LIX) at inducing an intracellular calcium increase in human neutrophils. After intradermal injection in mice, GCP-2(9-78) was also more effective than GCP-2(1-92)/LIX at inducing neutrophil infiltration. Similar to human IL-8 and GCP-2, murine GCP-2(9-78) and macrophage inflammatory protein-2 (MIP-2) induced calcium increases in both CXCR1 and CXCR2 transfectants. Murine GCP-2(9-78) could desensitize the calcium response induced by MIP-2 in human neutrophils and vice versa. Furthermore, MIP-2 and truncated GCP-2(9-78), but not intact GCP-2(1-92)/LIX, partially desensitized the calcium response to human IL-8 in human neutrophils. Taken together, these findings point to an important role of post-translationally modified GCP-2 to replace IL-8 in the mouse.

Amino Acid Sequence↗
PubMed2000

Kinetic analysis of the internalization and recycling of [3H]TRH and C-terminal truncations of the long isoform of the rat thyrotropin-releasing hormone receptor-1.

The C-terminal tail of the long splice variant of the rat thyrotropin-releasing hormone (TRH) receptor-1 (TRHR-1L) comprises around 93 amino acids. A series of C-terminal truncations was constructed and expressed transiently in HEK-293 cells. The extent of steady-state internalization of these in response to [(3)H]TRH was dependent upon the degree of truncation. Little effect was produced by deletion of the C-terminal to 50 amino acids, although there was a substantial decrease in the extent of internalization by deletion to 45-46 amino acids. The rate of internalization of TRHR-1L in response to ligand was substantially decreased by the acid-wash procedures often used in the analysis of cellular distribution of receptors with peptide ligands, and thus an alternative procedure using a Mes-containing buffer was employed in the present study. Apart from a truncation anticipated to eliminate post-translational acylation of the re-ceptor, which altered both the association and dissociation rates of [(3)H]TRH, the kinetics of ligand binding were unaffected by C-terminal truncation. Equally, the rate of recycling to the plasma membrane of internalized receptors was unaffected by C-terminal truncation. Although the extent of internalization of the full-length receptor was impaired by pre-exposure of cells to TRH, this was not true of C-terminal truncation mutants, which displayed limited steady-state internalization ratios. A mutant with a substantial C-terminal deletion also displayed decreased functional desensitization compared with the full-length receptor.

Amino Acid Sequence↗
PubMed2000

[Expression of 3'-truncated preS/S gene in transgenic mice].

The 3'-truncated preS/S region from HBV genome, encoding a transcriptional transactivator, was cloned and a recombination expression vector for 3'-truncated HBV preS/S sequences under the control of the CMV promoter was constructed by recombination DNA techniques. Then, the expression vector DNA was microinjected into pronuclei of fertilized mouse oocytes. Founders of transgenic mice harbouring the recombination gene which can be expressed were screened by polymerase chain reaction (PCR) at genomic DNA level and confirmed by ELISA andlysis at protein level. Two of 15 mice in one series of microinjections showed the expression of 3'-truncated preS/S gene from HBV genome. The expression vector of 3'-truncated preS/S gene might be helpful for further studies of relationship between the expression production of 3'-truncated preS/S sequence and HBV-associated oncogenesis in vitro. The transgenic mice with expressing 3'-truncated preS/S gene will provide new insight into its roles in the development of human hepatocelluar carcinoma (HCC) in vivo.

Animals↗
PubMed2002

[Truncated growth hormone receptor mutations function as dominant-negative inhibitors of the full-length receptor and cause genetic short stature].

Truncated growth hormone receptor (GHR) mutations that lack the majority of the cytoplasmic domain have been identified in familial short stature and same truncated GHR isoforms generated by alternative splicing in a number of normal human tissues. The binding affinity of the truncated GHR was similar to that seen for the full-length receptor and the truncated GHR showed a much greater expression on the cell surface, which is consistent with lack of internalization. These truncated receptors function as dominant-negative inhibitors of the growth hormone (GH) signal and generate large amounts of GH binding protein (GHBP). Thus, truncated GHR isoform may be important as a physiological regulator of GH signaling in addition to providing a mechanism for the production of GHBP.

Dwarfism, Pituitary↗
PubMed1992

Expression of truncated transcripts of the proto-oncogene c-fps/fes in human lymphoma and lymphoid leukemia cell lines.

The human c-fps/fes proto-oncogene is expressed as a transcript of about 3.0 kb in both normal and leukemic myeloid cells. We have detected truncated c-fps/fes transcripts of about 0.9 kb in a panel of human lymphoma and lymphoid leukemia cell lines, but not in normal untransformed hematopoietic cells. Analysis of the chromatin structure of the c-fps/fes gene revealed DNAase I-hypersensitive sites in the 5' region of the gene and in exon 16. The presence and absence of these sites correlates with the expression of the 3.0 kb and 0.9 kb c-fps/fes RNAs respectively. The truncated transcripts initiate at two distinct sites within exon 16 of the c-fps/fes gene. The genomic region 5' to the transcription initiation sites is G+C rich but does not contain typical promoter consensus sequences. Sequence analysis of a cDNA clone of the truncated c-fps/fes transcripts did not reveal any point mutation and the truncated transcripts are normally spliced using the regular splice donor and acceptor sites. A putative open reading frame encompasses the phosphotransfer motif and the autophosphorylation site of the fps/fes kinase domain. In vitro transcription/translation of a cDNA clone corresponding to the truncated c-fps/fes transcripts revealed a protein of 17 kDa. There are no translocations or rearrangements in or around the c-fps/fes gene in cell lines which express the truncated c-fps/fes transcripts. This alternative transcription of c-fps/fes may indicate a novel activation process of this proto-oncogene.

Base Sequence↗
PubMed1991

Increase in specific DNA binding by carboxyl truncation suggests a mechanism for activation of Myb.

Oncogenic forms of the c-myb protein (Myb) often exhibit amino-terminal and/or carboxyl-terminal truncations. When the transcriptional activity of these proteins was examined it was found that carboxyl-truncated Myb is more effective as a transcriptional activator than full-length or amino-truncated Myb. In order to determine the effect of such truncations on sequence-specific DNA binding, we synthesized murine Myb in vitro and assessed DNA binding by using a mobility-shift assay. Compared with the full-length protein no difference in binding was observed following deletion of the amino terminus, despite the removal of much of the first repeat of the DNA-binding domain. However, the specific DNA-binding capacity of carboxyl-truncated Myb was 4-6 times greater than that of the full-length protein; moreover, DNA binding was independent of a 'leucine zipper' motif present in Myb. These observations suggest that the increased transforming and transactivating potential of carboxyl-truncated Myb is due, at least in part, to increased sequence-specific DNA binding.

Base Sequence↗
PubMed1997

Metabolism of apolipoprotein B-100 in a kindred with familial hypobetalipoproteinemia without a truncated form of apoB.

Familial hypobetalipoproteinemia (FHBL) exists in three forms: a) FHBL genetically linked to truncated forms of apolipoprotein B (apoB); b) FHBL linked to the apoB gene but with no apoB truncations; and c) FHBL not linked to the apoB gene. Mean production rate (PR) of apoB-100 in FHBL subjects heterozygous for apoB truncations is approximately 30% of normal. In a 49-member D-kindred (FHBL phenotype defined as apoB < 40 mg/dl), no apoB truncations were detectable either by immunoblotting of plasma or by sequencing of relevant stretches of the apoB gene. Herein we report on the kinetic parameters of apoB-100-containing lipoproteins in four affected members of the D-kindred, and compare their kinetic values to 14 normal subjects, and 8 previously reported FHBL subjects heterozygous for various truncated forms of apoB. After an 8-h primed intravenous infusion of [13C]-leucine, enrichments of apoB-100 were assessed by gas chromatography-mass spectrometry and kinetic parameters were calculated by multicompartmental modeling. The affected members of the D-kindred had similar very low, intermediate, and low density lipoprotein (VLDL, IDL, and LDL) PRs as normal controls, but their fractional catabolic rates (FCR) for VLDL and LDL were approximately 2 and 3 times higher, respectively, than those of normals. By contrast in apoB truncation subjects, apoB-100 PRs were uniformly reduced, while apoB-100 FCRs were similar to normals. Thus, diverse physiologic mechanisms are responsible for the low apoB levels in these two different, genetically determined forms of FHBL.

Adolescent↗
PubMed1999

Increased truncated form of plasma tissue factor pathway inhibitor levels in patients with disseminated intravascular coagulation.

To evaluate that the relationship between the truncated form of tissue factor pathway inhibitor (TFPI) and the stage of disseminated intravascular coagulation (DIC), we measured the plasma levels of tissue factor (TF) antigen and the intact and truncated forms of TFPI antigens in 41 patients with DIC, 12 with pre-DIC, and 20 with non-DIC. The plasma TF and total TFPI antigen levels were significantly higher in patients with DIC than in non-DIC patients. Plasma levels of intact TFPI antigen in the pre-DIC groups were significantly lower than in the non-DIC and DIC groups. The truncated form of TFPI antigen levels in DIC patients were significantly increased compared with those in non-DIC and pre-DIC patients. The fact that the intact form of TFPI was decreased in pre-DIC patients compared with that in non-DIC patients, suggests that it is consumed in the pre-DIC state and that hypercoagulability occurs in pre-DIC patients. The increased level of the truncated form of TFPI in DIC patients may be attributed to proteolysis of the intact form of TFPI in these patients. The increased level of the truncated form of TFPI may be a useful index for the diagnosis of DIC.

Disseminated Intravascular Coagulation↗
PubMed1996

Amyloid precursor protein truncated at any of the gamma-secretase sites is not cleaved to beta-amyloid.

beta A4 secretion occurs upon processing of amyloid protein precursor (APP) by beta-secretase (N-terminus of beta A4) and gamma-secretase (C-terminus). To determine the sequence of these activities and the processing intermediate of beta A4, we expressed several truncated APP molecules in human HEK-293 cells. Immunofluorescence and biotinylation studies indicated that full-length APP or APP lacking the cytosolic domain both were located intracellularly, associated with the cell surface and secreted. APPs truncated after amino acid 40, 42, or 43 of beta A4 were not inserted into cell membranes, were found intracellularly but not on the cell surface, and were efficiently secreted into the culture medium. The secretion of APP truncated at amino acid 40 of beta A4 occurred without proteolytic processing. Neither beta A4 nor P3 (the product of the alpha-secretase) was secreted from any of the APP molecules truncated at the gamma-secretase sites. In sharp contrast to this, when the C-terminal 100 amino acids of APP were expressed (APP truncated at the N-terminus of beta A4), a robust beta A4 secretion was observed. Thus, the C-terminal fragment of APP produced by beta-secretase activity is likely to be the processing intermediate of beta A4.

Amino Acid Sequence↗
PubMed1999

Mutation screening of the entire coding regions of the TSC1 and the TSC2 gene with the protein truncation test (PTT) identifies frequent splicing defects.

Mutation analyses in tuberous sclerosis (TSC) have reported a wide variety of disease-causing aberrations in the two known predisposing genes, TSC1 and TSC2 on chromosomes 9q34 and 16p13, comprising mainly small mutations distributed over the entire genes. So far, all known TSC1 mutations as well as the majority of TSC2 mutations truncate the proteins hamartin and tuberin, respectively. We describe for the first time an RNA-based screening of the entire coding regions of both TSC genes for truncating mutations applying the protein truncation test (PTT). Simultaneous investigation of both TSC genes in a group of 48 unassigned TSC patients, which were previously tested to exclude large intragenic TSC2 rearrangements, revealed aberrant migrating polypeptides resulting from truncating mutations in nine TSC1 cases and in 16 TSC2 cases while three TSC2 cases showed enlarged proteins. TSC1 mutations include two nonsense mutations, four insertions, and three splice mutations. Nineteen mutations identified in TSC2 were composed of four different nonsense mutations in five patients, one deletion, one insertion, and seven different splicing aberrations due to at least eight different mutations found in 12 patients. Additional predicted truncating mutations according to PTT without possible identification of the causative alteration allowed assignment to TSC1 in one and TSC2 in seven cases. Twelve patients without abnormalities in the PTT are assumed to harbor missense mutations, probably in TSC2. The high proportion of TSC2 splicing aberrations strengthens the importance of intronic disease-causing mutations and the application of RNA-based screening methods to confirm their consequences.

Adolescent↗
PubMed2002

Novel mutations of APOB cause ApoB truncations undetectable in plasma and familial hypobetalipoproteinemia.

Familial hypobetalipoproteinemia (FHBL) is a genetic disorder characterized by low levels of apoB-100 and LDL cholesterol. Truncation-producing mutations of apoB (chromosome 2) are among several potential causes of FHBL in patients. Ten new families with FHBL linked to chromosome 2 were identified. In Family 8, a 4432delT in exon 26 produces a frame-shift and a premature stop codon predicted to produce a truncated apoB-30.9. Even though this truncation is just 10 amino acid shorter than the well-documented apoB-31, which is readily detectable in plasma, apoB-30.9 is undetectable. Most truncations shorter than apoB-30 are not detectable in plasma. In Family 34, an acceptor splicing mutation at position -1 of exon 14 changes the acceptor splice site AG to AA. Two families (Family 50 and 52) had mutations (apoB-9 and apoB-29) reported previously. In Family 98, a novel point mutation in exon 26 (11163T>G) causes a premature stop codon, and produces a truncated apoB-80.5 readily detectable in plasma. Sequencing of the ApoB gene in families 1, 5, 18, 58, and 59 did not reveal mutations.

Adult↗
PubMed2005

Dietary factors and truncating APC mutations in sporadic colorectal adenomas.

Inactivating mutations in APC are thought to be early, initiating events in colorectal carcinogenesis. To gain insight into the relationship between diet and inactivating APC mutations, we evaluated associations between dietary factors and the occurrence of these mutations in a Dutch case-control study of sporadic colorectal adenomas (278 cases; 414 polyp-free controls). Direct-sequencing was used to screen adenomas for mutations in the mutation cluster region of APC; truncating mutations were detected in 161 (58%) of the adenomas. Red meat consumption was significantly differently related to polyps with truncating APC mutation (APC(+) polyps) compared to polyps without truncating APC mutation (APC(-) polyps) (highest vs. lowest tertile, odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.3-1.0). High intake of red meat and fat seemed to increase the risk of APC(-) polyps only (APC(+) vs. controls: red meat, OR = 1.0, 95% CI = 0.6-1.6; fat, OR = 1.1, 95% CI = 0.6-1.9; APC(-) vs. controls: red meat, OR = 1.8, 95% CI = 1.0-3.1; fat, OR = 1.9, 95% CI = 1.0-3.7). Intake of carbohydrates was inversely associated with both polyp groups, most noticeably with APC(-) polyps. Most other evaluated dietary factors were not distinctively associated with a specific APC status. None of the dietary factors was specifically associated with a particular type of truncating APC mutation. Our data suggest that red meat and fat may increase the risk of APC(-) polyps in particular, whereas carbohydrates may especially decrease the risk of APC(-) polyps. However, most examined dietary factors do not appear to be specifically associated with the occurrence of truncating APC mutations in colorectal adenomas but seem to affect both pathways equally.

Adenoma↗
PubMed1988

Truncation of the human EGF receptor leads to differential transforming potentials in primary avian fibroblasts and erythroblasts.

The transforming capacity of the normal and mutant human EGF receptor (EGFR) was investigated in primary chicken cells. In fibroblasts, both N- and C-terminal truncations resulted in a weak, additive oncogenic activity. However, not even double truncations caused a v-erbB-like phenotype. Upon EGF-binding, on the other hand, both normal and C-terminally truncated EGFRs resembled v-erbB in their fibroblast transforming potential. In erythroblasts, N-terminal truncation was sufficient to induce constitutive self-renewal, which was enhanced by deletion of 32 C-terminal amino acids but abolished by a larger truncation of 202 amino acids. In contrast to the normal EGFR, the receptor lacking 32 C-terminal amino acids resembled v-erbB in conferring erythropoietin independence for spontaneous differentiation to the transformed erythroblasts. Our results indicate that the C-terminal domain of the EGFR is non-essential in fibroblast transformation, but seems to be crucial for both self renewal induction and specificity of receptor function in erythroblasts.

Animals↗
PubMed1990

Truncation of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) from Rhodospirillum rubrum affects the holoenzyme assembly and activity.

Truncations of the subunit of ribulose bisphosphate carboxylase/oxygenase (Rubisco) from Rhodospirillum rubrum were generated by site-directed mutagenesis to examine the role of the C-terminal tail section. Removal of the last and the penultimate alpha-helices in the tail section changes the quaternary structure of the protein. Electrophoretic and electron microscope analysis revealed that the truncated subunits assemble into an octamer, whereas the wild-type enzyme has a dimeric structure. The octomerization of the mutant protein is due to a hydrophobic patch exposed to the solvent by truncation of the subunit. The mutant protein thus consists of four dimers, bound end-to-end by hydrophobic interactions. Insertion of a polar amino acid in the hydrophobic patch by a L424 to N424 substitution restores the familiar dimeric structure. Truncation of the subunit is associated with a considerable decrease in catalytic activity. The mutants undergo carbamylation but bind the reaction intermediate analog, 2-carboxy arabinitol-1,5-bisphosphate, poorly. This indicates that loss of activity in the mutant is due to weakened substrate binding. These findings suggest that the mutations in the tail section of the subunit are transmitted to the active site, although the C-terminal region is far from the active site. On the basis of the crystal structure of Rubisco, we propose a model for how the truncations of the enzyme subunit induce conformational changes in one of the two phosphate binding sites.

Amino Acid Sequence↗
PubMed2006

Nuclear addressing provides a clue for the transforming activity of amino-truncated CCN3 proteins.

CCN3 is a founding member of the CCN (Cyr61, Ctgf, Nov) family of cell growth and differentiation regulators. These secreted proteins are key regulators in embryonic development, and are associated with severe pathologies including fibrotic diseases and cancers. CCN3 was discovered as a MAV integration site in an avian nephroblastoma. Previous work established that the amino-truncated protein expressed in this tumor was inducing morphological transformation of chicken embryo fibroblasts, whereas the full-length secreted CCN3 protein was inhibiting cell growth. Amino-truncated variants were identified in cancer cell lines. Since the lack of signal peptide was expected to alter the fate of the truncated proteins, we hypothesized that modifications of CCN3 subcellular addressing could be responsible for the oncogenic activities of CCN3. The CCN proteins are composed of four structural modules (IGFBP, TSP1, VWC, and CT). We report that amino-truncated variants of CCN3 are addressed to the nucleus and that the carboxyterminal (CT) module of CCN3 is responsible for the nuclear addressing. Furthermore, our data identify nuclear CCN3 variants as potential transcriptional regulators. In this context, the CT module confers on nuclear CCN3 proteins a negative regulatory effect on transcription. We propose that the nuclear localization of amino-truncated CCN3 proteins be correlated to oncogenicity.

Animals↗
PubMed2002

Truncation of the amino terminus of branching enzyme changes its chain transfer pattern.

Previous work has reported the production of an Escherichia coli branching enzyme with a 112-residue deletion at the amino terminal by limited proteolysis. Here, we study the chain transfer pattern of this enzyme. Gel-permeation chromatography of in vitro branched amylose shows that the truncated branching enzyme transfers fewer short chains (degree of polymerization [d.p.] <20) and a greater proportion of intermediate size chains (d.p. 30-90) than the native enzyme. High-performance anion-exchange chromatography (HPAEC) of the branching limited alpha-glucan product indicates that the truncated branching enzyme transfers a smaller proportion of chains with d.p. 4-11 and more chains longer than d.p. 12. Also, the genes encoding native or truncated branching enzyme were individually expressed in a branching enzyme-deficient mutant, AC71 (glgB(-)). By HPAEC analysis of the purified alpha-glucans we find that truncated branching enzyme transfers fewer chains of d.p. 5-11 and more chains longer than d.p. 12 relative to the full-length enzyme. These observations allow us to conclude that truncation of the amino-terminal domain has altered the branching pattern of the enzyme. Our results are consistent with the construction of hybrid branching enzymes from the maize isoforms.

1,4-alpha-Glucan Branching Enzyme↗
PubMed2002

Regulation of thioredoxin peroxidase activity by C-terminal truncation.

Thioredoxin peroxidase is a member of peroxiredoxin (Prx) family, which uses a thioredoxin (Trx) as an immediate electron donor for the reduction of peroxide. We have identified C-terminal truncated TPx from Schizosaccharomyces pombe and also have found the truncated form is significantly tenacious against the inactivation of H2O2 than the intact form. Peroxidase assay of a series of recombinant C-terminal truncation mutants (Delta192, Delta191, Delta188, Delta184, Delta176, and Delta165) revealed that TPx could be inactivated (Delta192), reactivated (Delta191-Delta176) and reinactivated (Delta165) by serial truncation from C-terminus. We did not find any significant kinetic difference among reactivated forms; however, distinctive loss of affinity to H2O2 (K(m) = 5 microM) than that of the intact form (<<5 microM, undeterminable) was monitored. Characterization of a series of Lys(191) point mutants manifested that the loss of affinity caused by a deprivation of positive charge born in Lys(191) and the loss of affinity resulted in the resistibility to H2O2. Disk inhibition assay with S. pombe cells overexpressing wild-type, Delta192 and Delta191 mutants evidenced that the truncated forms functioning in vitro as well as in vivo.

Amino Acid Sequence↗
PubMed1999

Engineered truncations in the Drosophila mastermind protein disrupt Notch pathway function.

The phenotypes and genetic interactions associated with mutations in the Drosophila mastermind (mam) gene have implicated it as a component of the Notch signaling pathway. However, its function and site of action within many tissues requiring Notch signaling have not been thoroughly investigated. To address these questions, we have constructed truncated versions of the Mam protein that elicit dominant phenotypes when expressed in imaginal tissues under GAL4-UAS regulation. By several criteria, these effects appear to phenocopy loss of function for the Notch pathway. When expressed in the notum, truncated Mam results in failure of lateral inhibition within proneural clusters and perturbations in cell fate specification within the sensory organ precursor cell lineage. Expression in the wing is associated with vein thickening and margin defects, including nicking and bristle loss. The truncation-associated wing margin phenotypes are modified by mutations in Notch and Wg pathway genes and are correlated with depressed expression of wg, cut, and vg. These data support the idea that Mam truncations have lost key effector domains and therefore behave as dominant-negative proteins. Coexpression of Delta or an activated form of Notch suppresses the effects of the Mam truncation, suggesting that Mam can function upstream of ligand-receptor interaction in the Notch pathway. This system should prove useful for the investigation of the role of Mam within the Notch pathway.

Animals↗