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)

Ubiquitin-mediated proteolysis is involved in the turnover of many short-lived regulatory proteins. This pathway leads to the covalent attachment of one or more multiubiquitin chains to target substrates which are then degraded by the 26S multicatalytic proteasome complex. Multiple classes of regulatory enzymes have been identified that mediate either ubiquitin conjugation or ubiquitin deconjugation from target substrates. Timed destruction of cellular regulators by the ubiquitin-proteasome pathway plays a critical role in ensuring normal cellular processes. This review provides multiple examples of key growth regulatory proteins whose levels are regulated by ubiquitin-mediated proteolysis. Pharmacological intervention which alters the half-lives of these cellular proteins may have wide therapeutic potential. Specifically, prevention of p53 ubiquitination (and subsequent degradation) in human papilloma virus positive tumors, and perhaps all tumors retaining wild-type p53 but lacking the retinoblastoma gene function, should lead to programmed cell death. Specific inhibitors of p27 and cyclin B ubiquitination are predicted to be potent antiproliferative agents. Inhibitors of IkappaB ubiquitination should prevent NFkappaB activation and may have utility in a variety of autoimmune and inflammatory conditions. Finally, we present a case for deubiquitination enzymes as novel, potential drug targets.
J Mol Med (Berl) 1997 Jan
PMID:The ubiquitin-mediated proteolytic pathway as a therapeutic area. 902 Mar 79

B-Myb belongs to a family of related transcription factors which share a unique DNA binding domain. B-Myb plays an important role in regulation of the cell cycle. Its expression is upregulated by the human papilloma virus HPV16 E7 oncoprotein. Overexpression of B-Myb can bypass p53-mediated cell cycle arrest. The founding member of the myb gene family, c-Myb, and A-Myb are involved in hematopoiesis and neurogenesis, respectively, and are both activators of gene transcription. Whether B-Myb is a transactivator or a repressor, however, has remained a matter of discussion. We reviewed the transactivation potential of B-Myb in yeast, taking advantage of the fact that inducible gene activation is an evolutionarily conserved process. By mutational analysis we localized a conserved activation domain in B-Myb. In vertebrate cells the transactivation potential of B-Myb is concealed by the C-terminal part of the protein. We show that the cell cycle regulators cyclin A and cyclin E activate B-Myb by eradicating the inhibition mediated by its carboxy-terminus. Our data suggest that in vertebrates the trans-activating function of B-Myb is regulated during the cell cycle and link Myb functions to cell cycle progression.
J Mol Med (Berl)
PMID:B-Myb, a repressed trans-activating protein. 942 11

Pterygium is a lesion of the corneoscleral limbus which tends to grow in size, often recurs after surgical excision and is associated with exposure to solar light. Additionally, a family history is frequently reported. Loss of heterozygosity (LOH), increased P53 expression and the presence of oncogenic viruses, such as human papilloma virus (HPV) and herpes simplex virus (HSV), have been detected in pterygia, supporting the possible neoplastic nature of the lesion. Co-infection by HSV and HPV as well as LOH at some loci have also been correlated with clinical features, such as postoperative recurrence and history of conjunctivitis. A possible model of pterygium formation is proposed, in which genetic predisposition, environmental factors and viral infection(s) participate in a multi-step process. Future research may lead to new ways of pterygium treatment such as anti-viral or gene therapy.
Int J Mol Med 2000 Jul
PMID:Molecular genetic alterations and viral presence in ophthalmic pterygium. 1085 Dec 63

Some forms of hexavalent chromium [Cr(VI)] are known to cause damage to respiratory-tract tissue and DNA and are thought to be human lung carcinogens. In general, Cr(VI) is mutagenic and carcinogenic at doses that also evoke some cell death, and we previously showed that the predominant mode of death is apoptosis. Because p53 has been shown to initiate apoptosis after genotoxic insults, the objective of these experiments was to determine whether p53 is activated in and necessary for apoptosis of normal diploid human lung fibroblasts (HLF cells) after chromium exposure. By using annexin(V) staining and fluorescent microscopy, we found that Cr(VI) caused up to 14% of HLF cells to undergo apoptosis within 24 h after exposure. In addition, by using western blotting, we found that p53 protein levels increased fourfold to sixfold after exposure to sodium chromate. Because the major function of p53 is as a transcription factor, it must be translocated from the cytoplasm to the nucleus after chromate exposure to be active. Immunofluorescence studies using an antibody against p53 showed that, after chromate exposure, p53 was located in the nucleus of the treated HLF cells. The necessity of p53 for chromium-induced apoptosis was examined in two ways. One approach used dermal fibroblasts from p53 wild-type, heterozygous, and null mice, and the other approach used HLF cells that were transiently transfected with the human papilloma virus E6 gene, which targets p53 for degradation and creates a functional p53-null cell. These studies showed that chromium-induced apoptosis was p53 dependent. Mol. Carcinog. 28:111-118, 2000.
Mol Carcinog 2000 Jun
PMID:Chromium(VI) induces p53-dependent apoptosis in diploid human lung and mouse dermal fibroblasts. 1090 Apr 68

Chromosomal double-strand breaks (DSBs) occurring in mammalian cells can initiate genomic instability, and their misrepairs result in chromosomal deletion, amplification, and translocation, common findings in human tumors. The tumor-suppressor protein p53 is involved in maintaining genomic stability. In this study, we demonstrate that the deficiency of wild-type p53 protein may allow unrepaired DSBs to initiate chromosomal instability. The human lymphoblastoid cell line TK6-E6 was established by transfection with human papilloma virus 16 (HPV16) E6 cDNA into parental TK6 cells via a retroviral vector. Abrogation of p53 function by E6 resulted in an increase in the spontaneous mutation frequencies at the heterozygous thymidine kinase (TK) locus but not at the hemizygous hypoxanthine phosphoribosyl transferase (HPRT) locus. Almost all TK-deficient mutants from TK6-E6 cells exhibited loss of heterozygosity (LOH) with the hemizygous TK allele. LOH analysis with microsatellite loci spanning the long arm of chromosome 17, which harbors the TK locus, showed that LOH extended over half of 17q toward the terminal end. Cytogenetic analysis of LOH mutants by chromosome painting indicated a mosaic of chromosomal aberrations involving chromosome 17, in which partial chromosome deletions, amplifications, and multiple translocations appeared heterogeneously in a single mutant. We speculate that spontaneous DSBs trigger the breakage-fusion bridge cycle leading to such multiple chromosome aberrations. In contrast, no chromosomal alterations were observed in TK-deficient mutants from TK6-20C cells expressing wild-type p53. In wild-type p53 cells, spontaneous DSBs appear to be promptly repaired through recombination between homologous chromosomes. These results support a model in which p53 protein contributes to the maintenance of genomic integrity through recombinational repair.
Mol Carcinog 2000 Aug
PMID:Requirement of wild-type p53 protein for maintenance of chromosomal integrity. 1097 90

Onconase, an anticancer ribonuclease, damages cellular tRNA and causes caspase-dependent apoptosis in targeted cells (M. S. Iordanov, O. P. Ryabinina, J. Wong, T. H. Dinh, D. L. Newton, S. M. Rybak, and B. E. Magun. Cancer Res. 60, 1983-1994, 2000). The proapoptotic action of onconase depends on its RNase activity, but the molecular mechanisms leading to RNA damage-induced caspase activation are completely unknown. In this study, we have investigated whether onconase activates two signal-transduction pathways commonly stimulated by conventional chemo- and radiotherapy, namely the stress-activated protein kinase (SAPK) cascade and the pathway leading to the activation of nuclear factor-kappa B (NF-kappaB). We found that, in all cell types tested, onconase is a potent activator of SAPK1 (JNK1 and JNK2) and SAPK2 (p38 MAP kinase), but that it is incapable of activating NF-kappaB. Inhibition of p38 MAP kinase activity with a pharmacological inhibitor, SB203580, demonstrated that p38 MAP kinase is not required for onconase cytotoxicity. Using explanted fibroblasts from mice that contain targeted disruption of both jnk1 and jnk2 alleles, we found that JNKs are important mediators of onconase-induced cytotoxicity. Surprisingly, following the immortalization of these same cells with human papilloma virus (HPV16) gene products E6 and E7, additional proapoptotic pathways (exclusive of JNK) were provoked by onconase. Our results demonstrate that onconase may activate proapoptotic pathways in tumor cells that are not able to be accessed in normal cells. These results present the possibility that the cytotoxic activity of onconase in normal cells may be reduced by blocking the activity of JNKs.
Mol Cell Biol Res Commun 2000 Aug
PMID:Differential requirement for the stress-activated protein kinase/c-Jun NH(2)-terminal kinase in RNAdamage-induced apoptosis in primary and in immortalized fibroblasts. 1117 Aug 43

Cervical carcinoma is etiologically associated with the human papilloma virus (HPV), HPV 16 and HPV 18 being the most common. Viral DNA is thought to persist mostly in the episomal form in early tumor development, and in the integrated form in carcinomas. This assumption was checked with a new method that discriminated between RNAs transcribed from episomal and integrated HPV DNAs. Both forms were detected in carcinomas of Russian patients regardless of the disease stage. The data were verified by two other methods. RNA with sequences of the HPV transforming gene E7 proved to be transcribed from either DNA form. The results suggest that HPV integration is not crucial for carcinoma progression.
Mol Biol (Mosk)
PMID:[Status of the human DNA papillomavirus in cervical tumors]. 1144 29

It has been reported that the p53Arg homozygous genotype could be a potential genetic risk factor for cancer. In this study we investigated the proportion of p53 codon 72 genotypes in patients with colon cancer and compared to a control population. A region of the p53 gene containing the polymorphic site was amplified by PCR and the genotypes were determined by restriction enzyme digestion. No significant difference was found between genotype frequencies in the study groups. Infection with human papilloma virus was also investigated in the tumor samples. HPV 18 and HPV 33 infection was observed in a considerable number of the tumor samples. Incidence of HPV infection did not show a correlation with the genotypes. Thus the p53 genotypes do not seem to be associated with risk of colon cancer or HPV infection.
Res Commun Mol Pathol Pharmacol 2001 Jul
PMID:P53 codon 72 genotypes in colon cancer. Association with human papillomavirus infection. 1145 82

The action of transforming proteins from small DNA tumor viruses seems to be remarkably similar between different viruses, as they all use pRb and p53 pathways as cellular targets. This leads to deregulation of host cell cycling, which in turn creates an environment favorable for viral replication. Based on this, we hypothesized that regulatory proteins from human papillomaviruses (HPVs) can functionally trans-complement viral DNA replication of adenoviruses deleted for the E1A and E1B genes (AdE1-). To test this, we constructed AdE1- vectors expressing the human papilloma virus 16 (HPV-16) proteins E6 and E7. Expression of both E6 and E7 from these vectors partially complemented adenoviral DNA replication activity in vitro, in SK-Hep1 cells and primary human astrocytes, as well as in vivo in mouse liver. AdE1- vectors expressing E6 and E7 also increased hepatocellular DNA synthesis in vivo. Efficient AdE1- DNA replication was detected in HPV-associated cervical carcinoma cells but not in primary human cells. Linking the expression of regulatory oncoviral proteins to DNA replication of E1-mutant adenoviruses may provide a rationale for antitumor strategies.
Mol Ther 2001 Sep
PMID:Human papilloma virus E6 and E7 proteins support DNA replication of adenoviruses deleted for the E1A and E1B genes. 1154 11

Pseudotyped retroviral vectors combine the advantages of broad host range, high expression, stable chromosomal integration, and ease of preparation. These vectors greatly facilitate delivery into mammalian cells of sequences encoding individual peptide inhibitors-including those with therapeutic utility-and inhibitor libraries. However, retroviral vectors vary in behavior, particularly with respect to expression levels in different cell lines. Expression level is especially important in transdominant experiments because the concentration of an inhibitor (for example, an expressed peptide) is one of the key determinants in the degree of complex formation between the inhibitor and its target. Thus, inhibitor concentration should have an impact on the expressivity and/or penetrance of an induced phenotype. Here, we compare several retroviral vectors and human cell lines for relative expression levels using a green fluorescent protein reporter. We show for a subset of these lines that cellular protein concentrations produced by single-copy vectors range up to about 2 microM. We also examine other variables that contribute to expression level, such as the nature of the expressed protein's carboxy terminus. Finally, we test the effect of increased concentration on phenotype with a nine-amino-acid peptide derived from the human papilloma virus protein E7 which overcomes E7-mediated cell growth.
Mol Ther 2001 Nov
PMID:Exogenous peptide and protein expression levels using retroviral vectors in human cells. 1170 76


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