Hypermethylation of the cell cycle inhibitor p15INK4b 3′-untranslated region interferes with its transcriptional regulation in primary lymphomas

Malumbres, Marcos; Castro, Ignacio Pérez de; Santos, Javíer; J, Fernández Piqueras; Pellicer, A.

doi:10.1038/sj.onc.1202299

Cited by 53 publications

(34 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since p15 Ink4b induces growth arrest associated with differentiation or apoptosis, it is not usually expressed in normal or transformed proliferating hematopoietic cells (Herman et al, 1997;Iravani et al, 1997;Malumbres et al, 1997;Uchida et al, 1997;Malumbres et al, 1999). In the present study, we found that transformed murine monocytic cells with exogenously expressed c-Myc were an exception.…”

Section: Discussionmentioning

confidence: 36%

Consistent inactivation of p19Arf but not p15Ink4b in murine myeloid cells transformed in vivo by deregulated c-Myc

Haviernik

Schmidt

et al. 2003

Oncogene

View full text Add to dashboard Cite

Cyclin-dependent kinase inhibitors p16 INK4a and p15 INK4b , encoded by the CDKN2A and B loci, play an important role in negative regulation of the cell cycle. Furthermore, p19 ARF also encoded by the CDKN2A locus, has been shown to regulate positively the p53 pathway leading to growth arrest and apoptosis. All three genes have been inactivated in human tumors. In myeloid cells, p15 INK4b mRNA is upregulated during cytokine-induced differentiation and/or growth arrest, and hypermethylation of the p15 INK4b gene promoter region is a common event in acute myeloid leukemia. In the present study, we examined murine monocyte/macrophage tumors with deregulated cmyc for evidence of Ink4 gene inactivation. p15 Ink4b mRNA and protein were detected in the majority of leukemias, and p16 Ink4a mRNA and protein were highly expressed in two of them. pRb was in a hypophosphorylated state in most of the neoplasms indicating that the Cdk inhibitors that were expressed in the cells were functional. The observed expression of p15 Ink4b is inconsistent with their proliferation state, although it might be expected to be expressed owing to the maturity of the cells. These data suggest, therefore, that deregulated cMyc bypasses the pRb restriction point and cell cycle arrest in these tumors. An examination of p19 Arf exons revealed deletions of the gene in up to 94% of the tumors. Since this gene shares exon 2 with p16 Ink4a , it is often difficult to determine which gene is the relevant tumor suppressor. However, the loss of only the p19 Arf -specific exon 1b was observed in a tumor that had normal p16 Ink4a protein expression. In addition, the p19 Arf -specific exon was deleted in another tumor that expressed a functional chimeric protein, p15Ex1-p16Ex2-3; it was demonstrated here that this fusion protein is capable of inducing G1 arrest. These data overall supports the hypothesis that the critical inactivation event in these hematopoietic neoplasms is elimination of p19 Arf , and not Ink4 function.

show abstract

Section: Discussionmentioning

confidence: 36%

Consistent inactivation of p19Arf but not p15Ink4b in murine myeloid cells transformed in vivo by deregulated c-Myc

Haviernik

Schmidt

et al. 2003

Oncogene

View full text Add to dashboard Cite

show abstract

“…It has been suggested that methylation of cytosine in CpG dinucleotides in the 5 0 and the 3 0 flanking region represses gene expression by preventing transcription factors from binding to their target. 13,22,23 In this study, we observed that the 5 0 region of the SDF1 gene was unmethylated even in PBMCs where the SDF1 gene was not expressed. As for the 3 0 UTR of the SDF1b gene, by contrast, we found site-specific demethylation in the region around the polymorphic site at np 801 in the EBV-transformed LCLs that express the SDF-1 mRNA.…”

Section: Discussionmentioning

confidence: 61%

The SDF1-G801A polymorphism is not associated with SDF1 gene expression in Epstein–Barr virus-transformed lymphoblastoid cells

2003

View full text Add to dashboard Cite

The effects of the SDF1-3 0 A on AIDS progression have been attributed to the altered amount of stromal cell-derived factor 1 (SDF-1). However, the contribution of the SDF1-G801A polymorphism to SDF-1 expression is still unclear. In contrast to fresh peripheral blood mononuclear cells (PBMCs), Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) express the SDF-1 mRNA. Using EBV-transformed LCLs from 42 individuals with different genotypes, we investigated the SDF-1 mRNA levels and methylation status in the SDF1 gene. Both in PBMCs and in EBV-transformed LCLs, CpG dinucleotides in the 5 0 region of the SDF1 gene were unmethylated. As for the 3 0 untranslated region (3 0 UTR), by contrast, CpG dinucleotides were methylated in PBMCs, whereas site-specific demethylation around the polymorphic site was detected in EBV-transformed LCLs. The levels of the demethylation were correlated with the SDF-1 mRNA levels. However, the genotype for the SDF1-G801A polymorphism did not significantly alter the SDF-1 mRNA levels. The allele preferences in transcription and methylation were also absent in the heterozygous cells. In conclusion, this study suggested a contribution of site-specific demethylation in the 3 0 UTR to the SDF1 gene expression, but did not show any evidence for the contribution of the SDF1-G801A polymorphism to the amount of the SDF-1 mRNA.

show abstract

“…A growing number of studies, however, have recently investigated the role of DNA methylation in the 3′UTR on the regulation of gene expression. [23][24][25][26] One of the first studies showing differential methylation in the 3′UTR region reported that hypermethylation of the cell cycle inhibitor gene p15INK4b interferes with its expression in primary lymphomas. 23 Hypomethylation of CCDN1 3′UTR DNA region, concomitant with an increased expression of the gene, was observed in many neuroblastoma cases.…”

Section: Function Of Methylation In 3′utr Sequencesmentioning

confidence: 99%

“…[23][24][25][26] One of the first studies showing differential methylation in the 3′UTR region reported that hypermethylation of the cell cycle inhibitor gene p15INK4b interferes with its expression in primary lymphomas. 23 Hypomethylation of CCDN1 3′UTR DNA region, concomitant with an increased expression of the gene, was observed in many neuroblastoma cases. 24 Similarly, methylation of Lhx8 DNA 3′UTR region was inversely correlated with the protein expression during different phases of oogenesis in the mouse.…”

Section: Function Of Methylation In 3′utr Sequencesmentioning

confidence: 99%

Functional DNA methylation in a transcript specific 3′UTR region of TrkB associates with suicide

et al. 2014

View full text Add to dashboard Cite

Hypermethylation of the cell cycle inhibitor p15INK4b 3′-untranslated region interferes with its transcriptional regulation in primary lymphomas

Cited by 53 publications

References 44 publications

Consistent inactivation of p19Arf but not p15Ink4b in murine myeloid cells transformed in vivo by deregulated c-Myc

Consistent inactivation of p19Arf but not p15Ink4b in murine myeloid cells transformed in vivo by deregulated c-Myc

The SDF1-G801A polymorphism is not associated with SDF1 gene expression in Epstein–Barr virus-transformed lymphoblastoid cells

Functional DNA methylation in a transcript specific 3′UTR region of TrkB associates with suicide

Contact Info

Product

Resources

About