Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoblastoma (Rb) protein promotes cell survival after DNA damage. We show here that the LxCxE binding site in Rb mediates both cell survival and cell-cycle arrest after DNA damage. Replication factor C (RF-C) complex plays an important role in DNA replication. We describe a novel function of the large subunit of RF-C in promoting cell survival after DNA damage. RF-Cp145 contains an LxCxE motif, and mutation of this motif abolishes the protective effect of RF-Cp145. The inability of wild-type RF-Cp145 to promote cell survival in Rb-null cells is rescued by Rb but not by Rb mutants defective in binding LxCxE proteins. RF-C thus enhances cell survival after DNA damage in an Rb-dependent manner.
Mol Cell 2001 Apr
PMID:The large subunit of replication factor C promotes cell survival after DNA damage in an LxCxE motif- and Rb-dependent manner. 1133 96

Replication factor C (RFC) is a heteropentameric sliding clamp loader protein essential for processive synthesis of DNA by eukaryotic DNA polymerases delta and epsilon. To study the interaction of RFC with 3' and 5' ends of the DNA primer, we have developed chemical photocrosslinking assay using a synthetic DNA gap and DNA primer-template structures. We have found that the radioactively labeled primers containing a photoreactive group at their 5' end could crosslink with the largest RFC subunit (RFC140) on primer-templates and DNA gap structures, but that 3' end photoreactive primers could only crosslink with RFC140 within the DNA gap structure. Addition of replication protein A (RPA) to the reaction mixture resulted in the crosslinking of RPA subunits and inhibited crosslinking of RFC140 using 3' but not 5' photoreactive primers present at the gap. The results suggest specific contacts between RFC140 and the 5' end of the DNA primer. Together with previous data, these experiments allow us to propose a model for the DNA polymerase switch during eukaryotic DNA replication.
J Mol Recognit
PMID:Localization of the large subunit of replication factor C near the 5' end of DNA primers. 1150 Sep 70

The desensitization of the GH-induced Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) signaling pathway plays a crucial role in GH regulation of hepatic genes. Previous studies have demonstrated that the inactivation of the GH-induced JAK2/STAT5 pathway is regulated by protein translation and suppressors of cytokine signaling (SOCS). In this study we sought to explore the relationships between endoplasmic reticulum stress, GH-induced JAK2/STAT5 activity and SOCS expression. 1,2-bis(o-Aminophenoxy)ethane-N,N,N,N-tetraacetic acid (acetoxymethyl)ester (BAPTA-AM), used to provoke endoplasmic reticulum stress, caused a drastic inhibition of protein translation that correlated with the phosphorylation of the eukaryotic translation initiation factor 2alpha. Both GH and BAPTA-AM caused a rapid induction of the transcription factor C/EBP homology protein (CHOP) and an additive effect was observed with combined treatment, which suggests a regulatory role of GH on endoplasmic reticulum stress. Endoplasmic reticulum stress did not interfere with the rapid GH activation of STAT5 DNA binding activity. However, BAPTA-AM prolonged the DNA binding activity of STAT5 without affecting STAT5 or JAK2 protein levels. GH-induced phosphorylation of JAK2 and STAT5 DNA binding activity were prolonged in the presence of BAPTA-AM, suggesting that endoplasmic reticulum stress prevents the inactivation of STAT5 DNA binding activity by modulating the rate of JAK2/STAT5 dephosphorylation. Like BAPTA-AM, the endoplasmic reticulum stressors dithiothreitol and A23187 also prolonged the GH-induced STAT5 DNA binding activity. We were not able to correlate BAPTA-AM effects to the GH-dependent expression of SOCS proteins or SOCS mRNA, suggesting that endoplasmic reticulum stress modulates the rate of JAK2/STAT5 dephosphorylation through mechanisms other than inhibition of SOCS expression. This study indicates that cellular stress may modulate transcription through the JAK/STAT pathway.
Mol Endocrinol 2001 Sep
PMID:Endoplasmic reticulum stress prolongs GH-induced Janus kinase (JAK2)/signal transducer and activator of transcription (STAT5) signaling pathway. 1151 96

The transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) is a strong inhibitor of cell proliferation. We found that C/EBPalpha directly interacts with cdk2 and cdk4 and arrests cell proliferation by inhibiting these kinases. We mapped a short growth inhibitory region of C/EBPalpha between amino acids 175 and 187. This portion of C/EBPalpha is responsible for direct inhibition of cyclin-dependent kinases and causes growth arrest in cultured cells. C/EBPalpha inhibits cdk2 activity by blocking the association of cdk2 with cyclins. Importantly, the activities of cdk4 and cdk2 are increased in C/EBPalpha knockout livers, leading to increased proliferation. Our data demonstrate that the liver-specific transcription factor C/EBPalpha brings about growth arrest through direct inhibition of cdk2 and cdk4.
Mol Cell 2001 Oct
PMID:C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. 1168 17

Binding of phosphorothioate-modified antisense oligodeoxynucleotides (AS ODNs) to target mRNAs is commonly thought to mediate RNA degradation or block of translation. Here we demonstrate cleavage of target mRNAs within the AS ODN binding region with subsequent degradation of the 5' but not the 3' cleavage product. Some, if not all, 3' mRNA fragments lacked a 5' cap structure, whereas their poly(A) tail length remained unchanged. Furthermore, they were efficiently translated into N-terminally truncated proteins as demonstrated in three settings: production of shortened hepadnaviral surface proteins, alteration of the subcellular localization of a fluorescent protein, and shift of the transcription factor C/EBPalpha isoform expression levels. Thus, AS treatment may result in the synthesis of N-truncated proteins with biologically relevant effects.
Mol Cell 2001 Oct
PMID:Generation of stable mRNA fragments and translation of N-truncated proteins induced by antisense oligodeoxynucleotides. 1168 7

Missense mutations in the COCH gene, which is expressed preferentially at high levels in the inner ear, cause the autosomal dominant sensorineural deafness and vestibular disorder, DFNA9 (OMIM 601369). By in situ hybridization of mouse and human inner ear sections, we find high-level expression of COCH mRNA in the fibrocytes of the spiral limbus and of the spiral ligament in the cochlea, and in the fibrocytes of the connective tissue stroma underlying the sensory epithelium of the crista ampullaris of the semicircular canals. A polyclonal antibody against the human COCH protein product, cochlin, was raised against the N-terminal 135 amino acid residues of cochlin, corresponding to the Limulus factor C-homology (cochFCH) domain; this domain harbors all five known point mutations in DFNA9. On western blots of human fetal cochlear extracts, anti-cochlin reacts with a cochlin band of the predicted full-length size as well as a smaller isoform. Immunohistochemistry performed with anti-cochlin shows staining predominantly in the regions of the fibrocytes of the spiral limbus and of the spiral ligament in mouse and in human fetal and adult tissue sections. These sites correspond to those areas that express COCH mRNA as determined by in situ hybridization, and to the regions of the inner ear which show histological abnormalities in DFNA9. The fibrocytes expressing mRNA and protein products of COCH are the very cell types which are either absent or markedly reduced and replaced by eosinophilic acellular material in temporal bone sections of individuals affected with DFNA9.
Hum Mol Genet 2001 Oct 15
PMID:Inner ear localization of mRNA and protein products of COCH, mutated in the sensorineural deafness and vestibular disorder, DFNA9. 1170 36

A gene coding for a protein containing two Scavenger Receptor Cysteine-Rich (SRCR) motifs, four Limulus factor C, Coch-5b2 and Lgl1 (LCCL) motifs; and one Polycystin-1, Lipoxygenase and Alpha Toxin (PLAT) motif was cloned from Plasmodium chabaudi and homologues identified in the P. falciparum and P. yoelii genome data bases. At least one of these sequence motifs (SRCR) has adhesive properties in other proteins, therefore, we propose to name this protein PSLAP for Plasmodium SRCR, LCCL Adhesive-like Protein. Southern blotting and chromosome analysis showed that pslap is a single copy gene on chromosome 14 in P. falciparum 3D7. pslap mRNA is strongly expressed in P. falciparum gametocytes, but was undetectable on Northern blots of RNA from the asexual blood stages. Polyclonal antibodies raised to different parts of PSLAP detected a protein expressed in late gametocytes, but not in the early stages of gametocytogenesis or asexual blood stages of P. falciparum. We suggest that PSLAP functions in the mosquito, for example, in modulation of the invertebrate host immune response or in protection against complement factors in the blood meal.
Mol Biochem Parasitol 2002 Apr 30
PMID:PSLAP, a protein with multiple adhesive motifs, is expressed in Plasmodium falciparum gametocytes. 1198 59

Malaria parasites suffer severe losses in the mosquito as they cross the midgut, haemolymph and salivary gland tissues, in part caused by immune responses of the insect. The parasite compensates for these losses by multiplying during the oocyst stage to form the infectious sporozoites. Upon human infection, malaria parasites are again attenuated by sustained immune attack. Here, we report a single copy gene that is highly conserved amongst Plasmodium species that encodes a secreted protein named PxSR. The predicted protein is composed of a unique combination of metazoan protein domains that have been previously associated with immune recognition/activation and lipid/protein adhesion interactions at the cell surface, namely: (i) scavenger receptor cysteine rich (SRCR); (ii) pentraxin (PTX); (iii) polycystine-1, lipoxygenase, alpha toxin (LH2/PLAT); (iv) Limulus clotting factor C, Coch-5b2 and Lgl1 (LCCL). In our assessment the PxSR molecule is completely novel in biology and is only found in Apicomplexa parasites. We show that PxSR is expressed in sporozoites of both human and rodent malaria species. Disruption of the PbSR gene in the rodent malaria parasite P. berghei results in parasites that form normal numbers of oocysts, but fail to produce any sporozoites. We suggest that, in addition to a role in sporogonic development, PxSR may have a multiplicity of functions.
Mol Microbiol 2002 Sep
PMID:A malaria scavenger receptor-like protein essential for parasite development. 1235 19

As an alternative to the scanning mechanism of initiation, the direct-internal-initiation mechanism postulates that the translational machinery assembles at the AUG start codon without traversing the entire 5' untranslated region (5'-UTR) of the mRNA. Although the existence of internal ribosome entry sites (IRESs) in viral mRNAs is considered to be well established, the existence of IRESs in cellular mRNAs has recently been challenged, in part because when testing is carried out using a conventional dicistronic vector, Northern blot analyses might not be sensitive enough to detect low levels of monocistronic transcripts derived via a cryptic promoter or splice site. To address this concern, we created a new promoterless dicistronic vector to test the putative IRES derived from the 5'-UTR of an mRNA that encodes the translation initiation factor eIF4G. Our analysis of this 5'-UTR sequence unexpectedly revealed a strong promoter. The activity of the internal promoter relies on the integrity of a polypyrimidine tract (PPT) sequence that had been identified as an essential component of the IRES. The PPT sequence overlaps with a binding site for transcription factor C/EBPbeta. Two other transcription factors, Sp1 and Ets, were also found to bind to and mediate expression from the promoter in the 5'-UTR of eIF4G mRNA. The biological significance of the internal promoter in the eIF4G mRNA might lie in the production of an N-terminally truncated form of the protein. Consistent with the idea that the cryptic promoter we identified underlies the previously reported IRES activity, we found no evidence of IRES function when a dicistronic mRNA containing the eIF4G sequence was translated in vitro or in vivo. Using the promoterless dicistronic vector, we also found promoter activities in the long 5'-UTRs of human Sno and mouse Bad mRNAs although monocistronic transcripts were not detectable on Northern blot analyses. The promoterless dicistronic vector might therefore prove useful in future studies to examine more rigorously the claim that there is IRES activity in cellular mRNAs.
Mol Cell Biol 2002 Nov
PMID:Regulation of gene expression by internal ribosome entry sites or cryptic promoters: the eIF4G story. 1237 Feb 85

The transcription factor C/EBPalpha is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and C/EBPalpha can block 12-O-tetradecanoylphorbol-13-acetate-induced monocytic differentiation of bipotential myeloid cells. In C/EBPalpha knockout mice, no mature granulocytes are present. A dramatic increase of c-Jun mRNA in C/EBPalpha knockout mouse fetal liver was observed. c-Jun, a component of the AP-1 transcription factor complex and a coactivator of the transcription factor PU.1, is important for monocytic differentiation. Here we report that C/EBPalpha downregulates c-Jun expression to drive granulocytic differentiation. An ectopic increase of C/EBPalpha expression decreases the c-Jun mRNA level, and the human c-Jun promoter activity is downregulated eightfold in the presence of C/EBPalpha. C/EBPalpha and c-Jun interact through their leucine zipper domains, and this interaction prevents c-Jun from binding to DNA. This results in downregulation of c-Jun's capacity to autoregulate its own promoter through the proximal AP-1 site. Overexpression of c-Jun prevents C/EBPalpha-induced granulocytic differentiation. Thus, we propose a model in which C/EBPalpha needs to downregulate c-Jun expression and transactivation capacity for promoting granulocytic differentiation.
Mol Cell Biol 2002 Dec
PMID:Downregulation of c-Jun expression by transcription factor C/EBPalpha is critical for granulocytic lineage commitment. 1244 86


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