Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In eukaryotic cells, nucleus-cytoplasm exchanges play an important role in genomic regulation. We have analyzed the localization of four nuclear antigens in different growth conditions: two replicative proteins, DNA polymerase alpha and proliferating cell nuclear antigen (PCNA), and two oncogenic regulatory proteins, c-Myc and c-Fos. A kinetic study of subcellular localization of these proteins has been done. In cultures in which cells were sparse, these proteins were detected in the nucleus. When proliferation was stopped by the high density of culture cells or by serum starvation, these proteins left the nucleus for the cytoplasm with different kinetics. DNA polymerase alpha is the first protein to leave the nucleus, with the PCNA protein, c-Fos, and c-Myc leaving the nucleus later. In contrast, during serum stimulation c-Fos and c-Myc relocalize into the nucleus before the replicative proteins. We also noticed that in sparse cell cultures, 10% of the cells exhibit a perinuclear staining for the DNA polymerase alpha, PCNA, and c-Myc proteins but not for c-Fos. This peculiar staining was also observed as an initial step to nuclear localization after serum stimulation and in vivo in Xenopus embryos when the G1 phase is reintroduced in the embryonic cell cycle at the mid-blastula stage. We suggest that such staining could reflect specific structures involved in the initiation of the S phase.
 ...
PMID:Comparative analysis of the intracellular localization of c-Myc, c-Fos, and replicative proteins during cell cycle progression. 135 52

The c-Myc protein is involved in cellular transformation and mitogenesis, but also works as a potent inducer of differentiation and programmed cell death. Max as an obligate heterodimeric partner for Myc mediates its functions as a specific transcriptional activator and a transforming protein. Mad and Mxi1 proteins both heterodimerize with Max and compete with each other for limiting amounts of Max. Transcriptional activation by Myc can be suppressed by increasing the amount of Mad or Mxi1. This report shows the expression pattern of these Myc related factors at the mRNA level in a small cell lung cancer (SCLC) cell line (GLC4) which is characterized by c-myc amplification and strong constitutive c-myc overexpression. We found these genes transcriptionally active but uninfluenced from high c-myc transcription. Max was constantly transcribed at a relatively low level during cell cycle progression. Mad and mxi1 mRNA was at a surprisingly high level in proliferating cells. Mad was further upregulated and mxi1 was downregulated to basal levels during serum starvation of the cells. We further analyzed the activity of c-fos, c-jun, c-myb and nm23 which are described to be involved in c-myc transcriptional activation, c-jun and c-fos were not constitutively activated and can be excluded as regulators. High steady state c-myc in contrast influences the serum stimulated transient activation mechanism of these two genes. We identified high copy number nm23 mRNA whose role as a putative c-myc transcriptional activator is under investigation. Our results indicate that constitutive overexpression of c-myc does not require the activity of the nuclear oncogenes tested and that the m-RNA expression pattern of functionally related proteins is not influenced.
 ...
PMID:Coexpression pattern of c-myc associated genes in a small cell lung cancer cell line with high steady state c-myc transcription. 765 39

When deprived of autocrine growth factors, Epstein-Barr virus (EBV)-immortalized B cells stop growing and die. In this study, we show that death of EBV-immortalized cells deprived of autocrine growth factors occurred by apoptosis. Cycloheximide, a protein synthesis inhibitor, inhibited apoptosis, suggesting that de novo protein synthesis is required. Because p53, Bcl-2, and c-Myc were previously implicated in the induction or prevention of apoptosis in other systems, we assessed their possible involvement here. Unlike normal cells that respond to growth factor deprivation by down-regulating c-Myc expression, EBV-immortalized cells continued to express c-Myc, p53, and Bcl-2 at levels comparable to those measured prior to starvation. Consistent with data demonstrating that c-Myc expression is sufficient to drive quiescent cells into the cell cycle, autocrine growth factor-deprived EBV-immortalized cells did not undergo growth arrest but rather continued to proliferate until death, which occurred randomly throughout the cell cycle. In contrast to EBV-immortalized B cells, normal peripheral blood B cells activated in vitro with anti-CD40 monoclonal antibody and interleukin 4 rapidly down-regulated c-Myc expression and underwent growth arrest in response to growth factors and serum deprivation. These findings demonstrated that c-Myc expression is deregulated in EBV-immortalized cells. Addition of antisense oligonucleotides to c-Myc specifically promoted the survival of starved EBV-immortalized cells and suppressed growth of nonstarved EBV-immortalized cells. Thus, deregulated expression of c-Myc in EBV-immortalized cells promotes proliferation and apoptosis following autocrine growth factor deprivation.
 ...
PMID:A role for deregulated c-Myc expression in apoptosis of Epstein-Barr virus-immortalized B cells. 780 56

We demonstrate in this paper that the G1 phase specific cell cycle regulator cyclin E is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo fibroblasts (REFs). Cyclin E/Ha-ras transformed cells are highly tumorigenic in synergeneic rats, are able to form colonies in soft agar and show protection towards apoptosis upon serum starvation or DNA damage compared to cells transformed by the combination of Myc, cyclin D1 or SV40 large T-antigen and Ha-ras. Lines that were established after cyclin E/Ha-ras or cyclin D1/Ha-ras transformation contain a large percentage of polyploid cells. This was not observed in cells transformed with other oncoproteins and Ha-ras pointing to an involvement of D- and E type cyclins in genomic instability. The cyclin dependent kinase inhibitors p21 and p27 but also p16 completely abrogate focus formation by cyclin E and Ha-ras suggesting that the oncogenic activity of cyclin E still requires functional G1 specific cyclin/CDK complexes. Moreover, inhibition of Myc function also blocks the oncogenic activity of cyclin E indicating a requirement of Myc for cyclin E function. The findings presented here demonstrate that cyclin E can act as an oncoprotein with a potential involvement in genomic instability and the prevention of cell death. Our data also present more evidence for a strict functional interdependency between G1 cyclin/CDK complexes and c-Myc.
 ...
PMID:Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4. 939 49

Adrenomedullin is a novel vasodilatory peptide originally isolated from pheochromocytoma. Recently, we found that adrenomedullin acts as an autocrine/paracrine apoptosis survival factor for rat endothelial cells. In the present study, we show that adrenomedullin induces the expression of Max, a heterodimeric partner of c-Myc, which may contribute to its ability to rescue endothelial cells from apoptosis. Max is a basic-helix-loop-helix-leucine zipper protein that forms heterodimers with its alternative partners, Mad and Mxi-1, to behave as an antagonist for Myc-Max heterodimer through competition for common DNA targets. The expression of Max is reported to be constitutive and more stable than c-Myc, and serum induces immediate c-Myc stimulation followed by modest Max up-regulation. In quiescent rat endothelial cells, adrenomedullin stimulated the expression of Max without affecting c-Myc. Quantitation with real-time quantitative PCR detected on the ABI Prism 7700 Sequence Detection System revealed that adrenomedullin and calcitonin gene-related peptide (CGRP), as well as serum, up-regulated Max mRNA levels and that down-regulation of Max mRNA after serum deprivation was prevented by adrenomedullin. Neither adrenomedullin nor CGRP affected c-Myc expression. Transfection of a Max-expressing plasmid into endothelial cells rescued the apoptosis induced by serum deprivation. Neutralization with anti-adrenomedullin antiserum or blockade with a CGRP receptor antagonist, CGRP(8-37), reduced Max mRNA levels in growing endothelial cells and enhanced apoptosis after serum starvation. Introduction of an antisense oligodeoxynucleotide against Max mRNA using transferrin receptor-operated transfer led to inhibition of both adrenomedullin-induced up-regulation of Max transcripts and its cell survival effect, whereas random, sense, or missense oligonucleotides were without effect. The negative regulation of E-box-driven transcription by adrenomedullin was demonstrated by using preproendothelin-1 promoter containing c-Myc-Max binding consensus sequence; the promoter activity of preproendothelin-1 was reduced by cotransfecting Max- and Mad-expressing plasmids as well as addition of adrenomedullin and CGRP. The present results demonstrate that adrenomedullin antagonizes serum deprivation-induced endothelial apoptosis by up-regulation of the max gene in an autocrine/ paracrine manner.
 ...
PMID:Induction of max by adrenomedullin and calcitonin gene-related peptide antagonizes endothelial apoptosis. 1044 8

Stra13 is a transcriptional repressor related within its basic helix-loop-helix domain with the Drosophila Hairy, Enhancer of Split, and the mouse Hes1 proteins that interact with the corepressor Groucho. Because Stra13 lacks the conserved WRPW motif for interaction with Groucho, we examined the function and mechanism of transcriptional repression mediated by Stra13 that exhibits several distinctive features. Here, we report that Stra13 expression is closely associated with cell growth arrest induced by several triggers such as retinoic acid and trichostatin A (TSA; a specific histone deacetylase inhibitor) as well as by serum starvation. Stra13 expression is transcriptionally repressed and maintained at a low level in cells through a negative autoregulatory mechanism that is brought about by its interaction with the corepressor histone deacetylase (HDAC1). This interaction requires the Stra13 C-terminal domain containing three alpha-helices, which are also functionally critical to its repressive activity. Thus, inhibition of HDAC activity by TSA abrogates Stra13-mediated repression of its promoter, resulting in induction of Stra13 expression that is coincident with TSA-induced growth arrest. Further, once induced, Stra13 strongly represses the expression of the cell proliferation-associated gene c-Myc through an HDAC1-independent pathway that involves its interaction with the basal transcription factor TFIIB. Our studies indicate that Stra13 may play a key role in signaling pathways that lead to growth arrest and terminal differentiation by repression of target genes via HDAC-dependent and HDAC-independent mechanisms.
 ...
PMID:Stra13 expression is associated with growth arrest and represses transcription through histone deacetylase (HDAC)-dependent and HDAC-independent mechanisms. 1073 69

Here we report, interleukin-6 (IL-6) dependent mouse B-cell hybridoma, 7TD1 cells underwent apoptotic cell death with the starvation of IL-6. First, 7TD1 cells cultured without IL-6 arrested at G0/G1 phase (maximum accumulation at 24 h ) of the cell cycle. After that, the parameters of apoptosis namely, decreased mitochondrial transmembrane potential (DeltaPsi(m)), activation of caspases, DNA fragmentation and morphological changes (condensed nucleus and formation of apoptotic bodies) were observed. As evidents by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses, down-regulation of Pim-1 (a serine/threonine kinase) and Bcl-2 was observed in the IL-6-depleted 7TD1 cells. There was no change in the expression of c-Myc, Bcl-xL and Mcl-1, even at 48 h of IL-6-depletion. Taken together, these results indicate that IL-6 withdrawn from the 7TD1 cells resulted in G0/G1 arrest and then caspase-dependent apoptosis via mitochondrial pathway by down-regulation of Pim-1 and Bcl-2, which may be essential for anti-apoptotic signals of IL-6.
 ...
PMID:Down-regulation of Pim-1 and Bcl-2 is accompanied with apoptosis of interleukin-6-depleted mouse B-cell hybridoma 7TD1 cells. 1116 76

Immortalization of B cells by Epstein-Barr virus (EBV) depends on the virally encoded EBNA2 protein. Although not related by sequence, the cellular Notch protein and EBNA2 share several biochemical and functional properties, such as interaction with CBF1 and the ability to activate transcription of a number of cellular and viral genes. Whether these similarities are coincidental or exemplify EBNA2 mimicry of evolutionarily conserved cellular signaling pathways is unclear. We therefore investigated whether activated forms of Notch could substitute for EBNA2 in maintaining the immortalized phenotype of EBV-infected B cells. To address this question, we devised a transcomplementation system using EREB2.5 cells. EREB2.5 cells are immortalized by EBV expressing a conditional estrogen receptor EBNA2 fusion protein (EREBNA2), and cellular proliferation is dependent on the availability of estrogen. Withdrawal of estrogen results in inactivation of EREBNA2, leading to growth arrest and eventually to cell death. Transduction of EREB2.5 cells with a lentiviral vector expressing wild-type EBNA2 rescued EREB2.5 cells from the growth-inhibitory effects of estrogen deprivation, in contrast to transduction with the lentivirus vector alone. EREB2.5 cells were also rescued by enforced expression of human Notch1IC after estrogen starvation, but this effect was restricted to cells expressing high levels of the transcription factor. Compared to wild-type EBNA2-expressing EREB2.5 cells, the Notch-expressing cells expanded more slowly after estrogen starvation, and once established, they continued to display a lower proliferation rate. Analysis of viral and cellular gene expression from transduced EREB2.5 cells after estrogen withdrawal indicated that both wild-type EBNA2- and Notch1IC-positive cells expressed c-Myc at levels similar to those found in parental EREB2.5 cells. However, the latter cells expressed LMP-1 far less efficiently than cells transduced with the wild-type EBNA2 gene. Cells rescued by either wild-type EBNA2 or Notch1IC expressed surface CD21 and CD23 proteins, but not CD10, indicating that induction of relevant type III latency markers was maintained. The data imply that both Notch and EBNA2 activate an important subset of cellular genes associated with type III latency and B-cell growth, while EBNA2 more efficiently induces important viral genes, such as LMP-1. Thus, exploitation of conserved Notch-related signaling pathways may represent a key mechanism by which EBNA2 contributes to EBV-induced cell immortalization.
 ...
PMID:Notch1IC partially replaces EBNA2 function in B cells immortalized by Epstein-Barr virus. 1139 May 91

Previously, we reported that c-Myc is glycosylated by O-linked N-acetylglucosamine at Thr-58, a known phosphorylation site and a mutational hot spot in lymphomas. In this paper, we describe the production and characterization of two Thr-58 site-specific antibodies and use them to examine the modification of Thr-58 in living cells. One antibody specifically reacts with the Thr-58-glycosylated form of c-Myc, and the other reacts only with unmodified Thr-58 in c-Myc. Using these antibodies together with a commercial anti-Thr-58-phosphorylated c-Myc antibody, we simultaneously detected three forms of c-Myc (Thr-58-unmodified, -phosphorylated, and -glycosylated). It has been reported that Thr-58 phosphorylation is dependent on a prior phosphorylation of Ser-62. Mutagenesis of Ser-62 to Ala showed a marked decrease of Thr-58 phosphorylation and a marked increase of Thr-58 glycosylation. Growth inhibition of HL60 cells by serum starvation increases Thr-58 glycosylation and correspondingly decreases its phosphorylation. Serum stimulation has the opposite effect upon the modification status of Thr-58. A candidate kinase responsible for Thr-58 phosphorylation is the glycogen synthase kinase 3 (GSK3). Lithium, a competitive inhibitor of GSK3, decreased Thr-58 phosphorylation and increased its glycosylation. Finally, we show that the Thr-58-phosphorylated form of c-Myc predominantly accumulates in the cytoplasm rather than the nucleus upon inhibition of proteasome activity. These data suggest that hierarchical phosphorylation of Ser-62 and Thr-58 and alternative glycosylation/phosphorylation of Thr-58 together regulate the myriad functions of c-Myc in cells.
 ...
PMID:Dynamic interplay between O-glycosylation and O-phosphorylation of nucleocytoplasmic proteins: alternative glycosylation/phosphorylation of THR-58, a known mutational hot spot of c-Myc in lymphomas, is regulated by mitogens. 1190 4

Effective cell cycle completion requires both Myc and E2F activities. However, whether these two activities interact to regulate cell survival remains to be tested. Here we have analysed survival of inducible c-Myc-overexpressing cell lines derived from U2OS human osteosarcoma cells, which carry wild-type pRb and p53 and are deficient for p16 and ARF expression. Induced U2OS-Myc cells neither underwent apoptosis spontaneously nor upon reconstitution of the ARF-p53 axis and/or serum-starvation. However, they died massively when concomitantly exposed to inhibitors of E2F activity, including a constitutively active pRb (RbDeltacdk) mutant, p16, a stable p27 (p27T187A) mutant, a dominant-negative (dn) CDK2, or dnDP-1. Similar apoptotic effect was observed upon down-modulation of endogenous E2Fs through overexpression of E2F binding site oligonucleotides in U2OS-Myc cells, upon expression of RbDeltacdk or dnDP-1 in the Myc-amplified HL-60 (ARF-; p53-) human leukemia cells, and upon co-transfection of Myc and RbDeltacdk in SAOS-2 (ARF+; p53-) human osteosarcoma cells but not in human primary fibroblasts. Consistent with these results, a dnp53 mutant did not abrogate the Myc-induced apoptotic phenotype, which instead strictly depended on caspase-3-like proteases and on Myc transcriptional activity. Our data indicate that in contrast to normal cells, Myc-overexpressing human cancer cells need E2F activity for their survival, regardless of their ARF and p53 status, a notion that may have important implications for antineoplastic treatment strategies.
 ...
PMID:E2F activity is essential for survival of Myc-overexpressing human cancer cells. 1222 53


1 2 3 4 Next >>