scholarly journals A Loss of Insulin-like Growth Factor-2 Imprinting Is Modulated by CCCTC-binding Factor Down-regulation at Senescence in Human Epithelial Cells

2004 ◽  
Vol 279 (50) ◽  
pp. 52218-52226 ◽  
Author(s):  
Vivian X. Fu ◽  
Steven R. Schwarze ◽  
Michelle L. Kenowski ◽  
Scott LeBlanc ◽  
John Svaren ◽  
...  
Keyword(s):  
Growth Factor ◽  
De Novo ◽  
Cellular Aging ◽  
Ctcf Binding ◽  
Paternal Allele ◽  
Ctcf Binding Site ◽  
Insulin Like Growth Factor ◽  
Down Regulation ◽  
Prostate Cell ◽  
Binding Factor

The imprinted insulin-like growth factor-2 (IGF2) gene is an auto/paracrine growth factor expressed only from the paternal allele in adult tissues. In tissues susceptible to aging-related cancers, including the prostate, a relaxation ofIGF2imprinting is found, suggesting a permissive role for epigenetic alterations in cancer development. To determine whetherIGF2imprinting is altered in cellular aging and senescence, human prostate epithelial and urothelial cells were passaged serially in culture to senescence. Allelic analyses using anIGF2polymorphism demonstrated a complete conversion of theIGF2imprint status from monoallelic to biallelic, in which the development of senescence was associated with a 10-fold increase inIGF2expression. As a mechanism, a 2-fold decrease in the binding of the enhancer-blocking element CCCTC-binding factor (CTCF) within the intergenicIGF2-H19region was found to underlie this switch to biallelicIGF2expression in senescent cells. This decrease in CTCF binding was associated with reduced CTCF expression in senescent cells. Node novoincreases in methylation at theIGF2CTCF binding site were seen. The forced down-regulation of CTCF expression using small interfering RNA in imprinted prostate cell lines resulted in an increase inIGF2expression and a relaxation of imprinting. Our data suggest a novel mechanism forIGF2imprinting regulation, that is, the reduction of CTCF expression in the control ofIGF2imprinting. We also demonstrate that altered imprinting patterns contribute to changes in gene expression in aging cells.

scholarly journals Down-regulation of insulin-like growth factor binding proteins and growth modulation in hepatoma cells by retinoic acid

Hepatology ◽  
1999 ◽  
Vol 29 (4) ◽  
pp. 1091-1098 ◽  
Author(s):  
Dae-Ghon Kim ◽  
Dae-yeol Lee ◽  
Baik-Hwan Cho ◽  
Kyung-Ran You ◽  
Mi-Young Kim ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Growth Factor ◽  
Binding Proteins ◽  
Hepatoma Cells ◽  
Insulin Like Growth Factor ◽  
Growth Modulation ◽  
Down Regulation ◽  
Factor Binding

scholarly journals Growth-condition-dependent regulation of insulin-like growth factor II mRNA stability

1996 ◽  
Vol 318 (1) ◽  
pp. 195-201 ◽  
Author(s):  
Wiep SCHEPER ◽  
Elly HOLTHUIZEN ◽  
John S P. SUSSENBACH
Keyword(s):  
Growth Factor ◽  
De Novo ◽  
Mrna Level ◽  
Growth Conditions ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Mobility Shift ◽  
Main Site ◽  
Factor Ii ◽  
Hep3b Cells

Insulin-like growth factor II (IGF-II) is synthesized in many tissues, but the main site of production is the liver. In this paper we show that IGF-II mRNA levels are dependent on the growth conditions of the cells. In Hep3B cells, serum deprivation leads to a marked increase in IGF-II mRNA levels. Serum stimulation of starved Hep3B cells induces a decrease in the amount of IGF-II mRNA, which is not caused by a change in promoter activity. IGF-II mRNAs are subject to endonucleolytic cleavage, a process that requires two widely separated elements in the 3´ untranslated region of the mRNA. Specific regions of these elements can form a stable stem structure which is involved in the formation of RNA–protein complexes. By employing electrophoretic mobility shift assays, two complexes have been identified in cytoplasmic extracts of Hep3B cells. The formation of these complexes is related to the growth conditions of the cells and is correlated with the regulation of IGF-II mRNA levels. Our data suggest that, depending on whether serum is present or absent, a transition from one complex to the other occurs. A decrease in the IGF-II mRNA level is also observed when IGF-I or IGF-II is added to serum-deprived Hep3B cells, possibly providing a feedback mechanism for IGF-II production. The serum-induced degradation of IGF-II mRNAs does not require de novo protein synthesis, and is abolished by rapamycin, an inhibitor of p70 S6 kinase.

Imprinting of insulin-like growth factor 2 is modulated during hematopoiesis

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3023-3028 ◽  
Author(s):  
Ian M. Morison ◽  
Michael R. Eccles ◽  
Anthony E. Reeve
Keyword(s):  
Growth Factor ◽  
Mononuclear Cells ◽  
Model Systems ◽  
Paternal Allele ◽  
Parental Origin ◽  
Insulin Like Growth Factor ◽  
Specific Expression ◽  
Peripheral Blood Mononuclear ◽  
Multistep Process

The transcription of insulin-like growth factor 2 (IGF-2) is affected by genomic imprinting, a multistep process through which the parental origin of a gene influences its transcription. The maternal copy of IGF-2 is silenced in most human tissues, but in the choroid plexus and the adult liver both alleles of IGF-2 are expressed. This study shows that though in peripheral blood mononuclear cells IGF-2shows paternal allele-specific expression, in total bone marrow both alleles are transcribed. This modulation of imprinting is not attributable to use of the P1 promoter, because transcription from the P3 promoter occurred from both alleles. These results suggest that transcriptional recognition of the IGF-2 imprint can be modulated during hematopoiesis and may facilitate the development of in vitro model systems to study the transcriptional recognition of a genomic imprint.

scholarly journals ADP-ribose polymer depletion leads to nuclear Ctcf re-localization and chromatin rearrangement1

2013 ◽  
Vol 449 (3) ◽  
pp. 623-630 ◽  
Author(s):  
Tiziana Guastafierro ◽  
Angela Catizone ◽  
Roberta Calabrese ◽  
Michele Zampieri ◽  
Oliviano Martella ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Nuclear Pore Complex ◽  
De Novo ◽  
Nuclear Organization ◽  
Ctcf Binding ◽  
Nuclear Pore ◽  
Active Chromatin ◽  
Lamin B1 ◽  
Binding Factor ◽  
Parp Activity

Ctcf (CCCTC-binding factor) directly induces Parp [poly(ADP-ribose) polymerase] 1 activity and its PARylation [poly(ADPribosyl)ation] in the absence of DNA damage. Ctcf, in turn, is a substrate for this post-synthetic modification and as such it is covalently and non-covalently modified by PARs (ADP-ribose polymers). Moreover, PARylation is able to protect certain DNA regions bound by Ctcf from DNA methylation. We recently reported that de novo methylation of Ctcf target sequences due to overexpression of Parg [poly(ADP-ribose)glycohydrolase] induces loss of Ctcf binding. Considering this, we investigate to what extent PARP activity is able to affect nuclear distribution of Ctcf in the present study. Notably, Ctcf lost its diffuse nuclear localization following PAR (ADP-ribose polymer) depletion and accumulated at the periphery of the nucleus where it was linked with nuclear pore complex proteins remaining external to the perinuclear Lamin B1 ring. We demonstrated that PAR depletion-dependent perinuclear localization of Ctcf was due to its blockage from entering the nucleus. Besides Ctcf nuclear delocalization, the outcome of PAR depletion led to changes in chromatin architecture. Immunofluorescence analyses indicated DNA redistribution, a generalized genomic hypermethylation and an increase of inactive compared with active chromatin marks in Parg-overexpressing or Ctcf-silenced cells. Together these results underline the importance of the cross-talk between Parp1 and Ctcf in the maintenance of nuclear organization.

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