Biomedical subjects

O Petrenko

Publications and source records attributed to O Petrenko.

8 recordsLinked to original sources

PubMed2005

MIF loss impairs Myc-induced lymphomagenesis.

Macrophage migration inhibitory factor (MIF) is a potent regulator of inflammation and cell growth. Using the Emu-Myc lymphoma mouse model, we demonstrate that loss of MIF markedly delays the onset of B-cell lymphoma development in vivo. The molecular basis for this MIF-loss-induced phenotype is the perturbed DNA-binding activity of E2F factors and the concomitantly enhanced tumor suppressor activity of the p53 pathway. Accordingly, premalignant MIF-null Emu-Myc B-cells are predisposed to delayed S-phase progression and increased apoptosis. MIF-deficient lymphomas that do arise under these conditions contain frequent ARF deletions and p53 inactivating mutations. Conversely, MIF expression is retained in tumors developed by wild-type Emu-Myc animals, and the presence of one or both MIF alleles is sufficient to accelerate the development of Myc-induced lymphomas. Collectively, these results indicate that MIF promotes Myc-mediated tumorigenesis, at least in the B-lymphoid compartment, and implicate MIF as a mediator of malignant cell growth in vivo.

Animals↗

PubMed2003

The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting.

Macrophage migration inhibitory factor (MIF) is a mediator of host immunity and functions as a high, upstream activator of cells within the innate and the adaptive immunological systems. Recent studies have suggested a potentially broader role for MIF in growth regulation because of its ability to antagonize p53-mediated gene activation and apoptosis. To better understand MIF's activity in growth control, we generated and characterized a strain of MIF-knockout (MIF-KO) mice in the inbred, C57BL/6 background. Embryonic fibroblasts from MIF-KO mice exhibit p53-dependent growth alterations, increased p53 transcriptional activity, and resistance to ras-mediated transformation. Concurrent deletion of the p53 gene in vivo reversed the observed phenotype of cells deficient in MIF. In vivo studies showed that fibrosarcomas induced by the carcinogen benzo[alpha]pyrene are smaller in size and have a lower mitotic index in MIF-KO mice relative to their WT counterparts. The data provide direct genetic evidence for a functional link between MIF and the p53 tumor suppressor and indicate an important and previously unappreciated role for MIF in carcinogenesis.

Alleles↗

PubMed2000

Complementation of Myc-dependent cell proliferation by cDNA expression library screening.

The targeted knockout of the c-myc gene from rat fibroblasts leads to a stable defect in cell proliferation. We used complex cDNA libraries expressed from retroviral vectors and an efficient sorting procedure to rapidly select for cDNAs that can restore the growth rate of c-myc deficient cells. All of the biologically active cDNAs contained either c-myc or N-myc, suggesting that no other cellular genes can effectively bypass the requirement for c-myc in fibroblast proliferation. This approach provides a powerful screening method for cell cycle changes in genetically defined systems.

Animals↗

PubMed1999

The molecular characterization of the fetal stem cell marker AA4.

We have identified and characterized the stem cell antigen AA4. This molecule is a type I transmembrane protein whose overall structure suggests a role in cell adhesion. During fetal ontogeny (days 9-14 of development), AA4 is expressed in three major cell types: vascular endothelial cells, aorta-associated hematopoietic clusters, and primitive fetal liver hematopoietic progenitors. In the adult, AA4 is abundant in lung, heart, and whole bone marrow. In the adult hematopoietic compartment, aa4 transcripts are present in bone marrow CD34(-/lo) Lin- Sca-1+ c-Kit+ and CD34hi Lin- Sca-1+ c-Kit+ stem and progenitor cell subsets. Our observations suggest that AA4 plays a role in cell-cell interactions during hematopoietic and vascular development.

3T3 Cells↗

PubMed1998

A chicken c-Rel-estrogen receptor chimeric protein shows conditional nuclear localization, DNA binding, transformation and transcriptional activation.

In this report, we characterize the biological and biochemical properties of a conditional protein containing chicken c-Rel fused to the hormone-binding domain of the human estrogen receptor. This chimeric c-RelER protein causes estrogen-dependent, but otherwise c-Rel-specific, transformation of avian fibroblasts in vitro. Our results demonstrate that c-RelER heterodimerizes with wild-type c-Rel and forms specific complexes with IkappaB-alpha. Estrogen causes translocation of c-RelER to the nucleus and stabilizes its binding to DNA. Hormone-activated c-RelER induces transcription of at least four cellular genes that are constitutively active in wild-type c-Rel-transformed fibroblasts. Two distinct cell populations were examined that differed with respect to their growth phenotypes. The growth of fibroblasts with moderate expression levels of c-RelER was stimulated by estrogen. In contrast, the addition of estrogen to cells with high cRelER expression levels resulted in inhibition of cytokinesis and the arrest of growth. The carboxy terminal transactivation domain of c-Rel was required for the induction of these effects since neither v-Rel nor c-Rel deletion mutants were able to induce similar changes. Taken together, our results demonstrate that high levels of c-Rel expression can affect cell cycle control and/or cytokinesis. Furthermore, they also indicate that the biological properties of c-Rel in cell growth and differentiation will potentially differ depending on the level of expression.

Animals↗

PubMed1997

Characterization of changes in gene expression associated with malignant transformation by the NF-kappaB family member, v-Rel.

In this study, alterations in gene expression patterns have been examined in v-Rel-transformed avian bone marrow cells. Using a conditional v-Rel estrogen receptor chimera (v-RelER) which transforms cells in an estrogen-dependent manner, we constructed subtraction cDNA libraries from v-RelER-transformed bone marrow cells. Several different sequences were identified whose expression was altered upon hormone activation of v-RelER. These include two genes related to the MIP-1 chemokine family (mip-1beta and a tca3 homologue), a cell surface antigen sca-2 and the transcription factor nfkb1. The expression of each gene was assayed in a number of wild-type and mutant v-Rel-expressing fibroblast and hematopoietic cells. All v-Rel-transformed hematopoietic cells tested express high levels of nfkb1 and sca-2. In fibroblasts, wild-type v-Rel induced expression of mip-1beta and nfkb1, while nontransforming mutants of v-Rel failed to do so, suggesting a role for these two genes in v-Rel mediated transformation. Finally, these genes are expressed at high levels in cells overexpressing wild-type and truncated forms of c-Rel, implying that v-Rel transforms, in part, by induction of c-Rel target genes.

Animals↗

PubMed1995

Isolation of a cDNA encoding a novel chicken chemokine homologous to mammalian macrophage inflammatory protein-1 beta.

A cDNA encoding a novel chicken chemokine homologous to mammalian chemokine macrophage inflammatory protein 1 beta (MIP-1 beta) was isolated and characterised. The cDNA encodes a protein which is 75-80% homologous to human and mouse MIP-1 beta. All conserved amino acids characteristic of the mammalian chemokine family have been evolutionarily preserved in chicken MIP-1 beta, suggesting similar protein folding patterns and functional properties.

Amino Acid Sequence↗

PubMed1993

Two insulin genes are present in the salmon genome.

According to the accepted hypothesis, polyploid evolution is necessary to achieve meaningful gene duplication. Some fish, namely those belonging to the suborder Salmonidae, appear to be autotetraploid species that probably originated from a diploid ancestor relatively recently and that appear to be progressing toward diploidization to various degrees. The Pacific chum salmon (Oncorhynchus keta) has almost completed this process of diploidization. Thus, with regard to practically any gene product, theory predicts a freshly diploidized, autotetraploid species to possess twice the number of gene loci as diploid animals. Here we show that the chum salmon genome contains two nonallelic insulin genes that are both expressed in chum salmon Brockman bodies. Nucleotide sequence analysis reveals structural diversification of this pair of duplicated genes.

Animals↗