Reappraisal of serum starvation, the restriction point, G0, and G1 phase arrest points

Cooper, Stephen

doi:10.1096/fj.02-0352rev

Cited by 136 publications

(117 citation statements)

References 31 publications

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“…We observed that about 10% of PRL-3-expressing cancer cells could take up antibodies in culture, and this uptake was enhanced 6-fold upon serum starvation (22). Serum starvation is used to arrest cells at G 1 and G 0 phases (23). It is possible that particular stages (perhaps G 1 -G 0 ) of the cell cycle contribute to the ability of cells to take up the antibodies.…”

Section: Possible Mechanisms For Antibody Targeting Of Intracellular mentioning

confidence: 94%

Awaiting a New Era of Cancer Immunotherapy

Hong

Zeng²

2012

Cancer Research

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A major challenge in cancer therapy is the lack of specificity for cancer cells. Antibody-based therapies have better specificity and, thus, improved efficacy over standard chemotherapy regimens. Monoclonal antibodies (mAb) constitute the most rapidly growing class of human therapeutics and are proven agents for recognizing and destroying malignant cells. However, the development of antibody therapies has focused only on targeting extracellular (cell-surface or secreted) proteins rather than intracellular targets (within cells, such as phosphatases and/or kinases and transcription factors), because antibodies are generally believed to be too large to enter cells, resulting in a large untapped source of intracellular therapeutic targets. Recently, we presented evidence that suggests that intracellular proteins with high expression in cancer cells are useful targets for mAb-based or vaccination immunotherapies, thus challenging current understanding. Here, we further discuss the concept and future uses of these immunotherapies against a large pool of intracellular oncoproteins for cancer therapy. This line of research has the potential to vastly expand the field of antibody therapy and usher in a new era of cancer vaccines. Cancer Res; 72(15); 3715-9. Ó2012 AACR.

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Section: Possible Mechanisms For Antibody Targeting Of Intracellular mentioning

confidence: 94%

Awaiting a New Era of Cancer Immunotherapy

Hong

Zeng²

2012

Cancer Research

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“…Serum deprivation of cells is known to alter the expression of several genes that are involved in cell proliferation and differentiation (Mandl et al, 2007;Muise-Helmericks et al, 1998). Serum starvation typically causes cell cycle arrest (G0 arrest or quiescence) eventually leading to senescence, apoptosis or cellular differentiation (Alexandre et al, 2000;Cooper, 2003;Simm et al, 1997). Interestingly, upon serum starvation, the number of GRC-RNA foci within the nuclei was dramatically decreased (5-8 instead of 50-60) but the existing nuclear foci became larger and more prominent (Fig.…”

Section: Grc-rna Nuclear Foci Number Is Altered During Cell Differentmentioning

confidence: 99%

Polypurine-repeat-containing RNAs: a novel class of long non-coding RNA in mammalian cells

Zheng

Shen

Tripathi

et al. 2010

Journal of Cell Science

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SummaryIn higher eukaryotic cells, long non-protein-coding RNAs (lncRNAs) have been implicated in a wide array of cellular functions. Cellor tissue-specific expression of lncRNA genes encoded in the mammalian genome is thought to contribute to the complex gene networks needed to regulate cellular function. Here, we have identified a novel species of polypurine triplet repeat-rich lncRNAs, designated as GAA repeat-containing RNAs (GRC-RNAs), that localize to numerous punctate foci in the mammalian interphase nuclei. GRC-RNAs consist of a heterogeneous population of RNAs, ranging in size from ~1.5 kb to ~4 kb and localize to subnuclear domains, several of which associate with GAA.TTC-repeat-containing genomic regions. GRC-RNAs are components of the nuclear matrix and interact with various nuclear matrix-associated proteins. In mitotic cells, GRC-RNAs form distinct cytoplasmic foci and, in telophase and G1 cells, localize to the midbody, a structure involved in accurate cell division. Differentiation of tissue culture cells leads to a decrease in the number of GRC-RNA nuclear foci, albeit with an increase in size as compared with proliferating cells. Conversely, the number of GRC-RNA foci increases during cellular transformation. We propose that nuclear GRC-RNAs represent a novel family of mammalian lncRNAs that might play crucial roles in the cell nucleus.Key words: Non-coding RNAs, Nuclear domains, Nuclear matrix, Triplex repeats, Midbody Journal of Cell ScienceRNAs) that are distributed throughout the nucleus in a micropunctate pattern. GRC-RNAs primarily consist of polypurine repeats and are heterogeneous in size, ranging from 1.5-4 kb. GRC-RNAs associate with the nuclear matrix and interact with several bona fide nuclear matrix proteins. Our studies further indicate that the nuclear GRC-RNA foci is altered in cells that either are highly proliferating or are cell-cycle-arrested owing to serum deprivation. We propose that GRC-RNAs are novel members of the nrRNA family of RNAs that interact with components of the nuclear matrix and play crucial structural roles in the maintenance of the nuclear matrix and/or regulate gene expression. Results GRC-RNAs are members of the nrRNA family of lncRNAsRNA in situ hybridization studies have previously cataloged~850 lncRNAs that are expressed in specific cell types or in specific subcellular compartments within the adult mouse brain (Lein et al., 2007;Mercer et al., 2008). To gain further insight into the cellular function of these novel ncRNAs, we analyzed their distribution in various mammalian cell lines by RNA-FISH (fluorescent in situ hybridization). One of these ncRNAs (EST clone AK082015; ~2.2 kb) showed a punctate distribution in the nucleus of mouse NIH-3T3 cells (Fig. 1A). In most of the cells, apart from numerous nuclear foci, 2-5 distinct brightly labeled GRC-RNA-positive foci were also observed in the cytoplasm (see arrows in Fig. 1A; supplementary material Fig. S1B,C). To identify the minimal region of the cDNA probe that hybridized to the nuclear foci-associa...

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“…It is generally believed that serum-starved cells are arrested in G 1 or G 0 phase, with most of the genes functioning at their basal expression level (53)(54)(55). However, there are some reports showing that serum starvation leads to up-regulation of certain genes.…”

Section: Transcriptional Regulation Of Sirp␣1 By Egfr Signalingmentioning

confidence: 99%

Transcriptional Regulation of Signal Regulatory Protein α1 Inhibitory Receptors by Epidermal Growth Factor Receptor Signaling

Kapoor¹,

Kapitonov²,

O’Rourke

2004

Cancer Research

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Signal regulatory protein (SIRP) ␣1 is a membrane glycoprotein and a member of the SIRP receptor family. These transmembrane receptors have been shown to exert negative effects on signal transduction by receptor tyrosine kinases via immunoreceptor tyrosine-based inhibitory motifs in the carboxyl domain. Previous work has demonstrated that SIRPs negatively regulate many signaling pathways leading to reduction in tumor migration, survival, and cell transformation. Thus, modulation of SIRP expression levels or activity could be of great significance in the field of cancer therapy. The aim of the present study was to determine the factors that regulate levels of SIRP␣1 in human glioblastoma cells that frequently overexpress the epidermal growth factor receptor (EGFR) because SIRPs have been shown to negatively regulate EGFR signaling. Northern blot analysis and immunoprecipitation assays showed variable expression levels of endogenous SIRP␣ transcripts in nine well-characterized glioblastoma cell lines. We examined SIRP␣1 regulation in U87MG and U373MG cells in comparison with clonal derivatives that express a truncated form of erbB2, which negatively regulates EGFR signaling by inducing the formation of nonfunctional heterodimeric complexes. Mutant erbB2-expressing cells contained more SIRP␣1 mRNA when compared with the parental cells in presence or absence of serum. Similarly, immunoprecipitation assays showed increased SIRP␣1 protein levels in erbB-inhibited cells when compared with parental cells. Messenger RNA stability assays revealed that the increased mRNA levels in EGFR-inhibited cells were due to an induction of transcription. Consistent with this finding, expression of the erbB2 mutant receptor up-regulated SIRP␣1 promoter activity in all cell lines tested. Interestingly, pharmacological inhibition of the kinase activities of EGFR, erbB2, and src and activation of mitogen-activated protein kinase, but not phosphatidylinositol 3-kinase, significantly up-regulated SIRP␣1 promoter activity. Based on these observations, we hypothesize that down-modulation of EGFR signaling leads to transcriptional up-regulation of the inhibitory SIRP␣1 gene. These data may be important in the application of erbB-inhibitory strategies and for design of therapies for the treatment of glial tumors and other epithelial malignancies.

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Reappraisal of serum starvation, the restriction point, G0, and G1 phase arrest points

Cited by 136 publications

References 31 publications

Awaiting a New Era of Cancer Immunotherapy

Awaiting a New Era of Cancer Immunotherapy

Polypurine-repeat-containing RNAs: a novel class of long non-coding RNA in mammalian cells

Transcriptional Regulation of Signal Regulatory Protein α1 Inhibitory Receptors by Epidermal Growth Factor Receptor Signaling

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