Transcriptional targets of p16INK4A in melanoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE7153 | GEO | 2007/10/01
SECONDARY ACCESSION(S): PRJNA98269
REPOSITORIES: GEO
Similar Datasets
Project description:Expression profiles of 17 melanoma cell lines were analysed to identify genes differentially expressed between cell lines harbouring wild-type or mutant p16INK4A. Relevant paper: Pavey et al. (2007). Note: all of these cell lines contained wild-type p14ARF, so that the transcriptional effects of p16INk4A could be determined without interference from p14ARF. Experiment Overall Design: The aim of this study was to identify genes which are transcriptional targets of p16INK4A in melanoma.
2008-06-15 | E-GEOD-7153 | biostudies-arrayexpress
Project description:35 Melanoma cell lines hybridized to Affymetrix Hu133_Plus 2 microarrays were analysed for genes differentially expressed between cell lines carrying wild-type p14ARF and those with mutant 14ARF. All of these cell lines contained wild-type p53 (so that the effects of p14ARF mutations could be analysed without contamination from p53). Experiment Overall Design: The aim of this study was to identify downstream effectors of p14ARF in melanoma. Relevant paper: Packer et al. (2007) Int J Cancer.
2008-06-15 | E-GEOD-7152 | biostudies-arrayexpress
Project description:63 melanoma cell lines hybridized to Affymetrix Hu133_Plus 2 oligo arrays. The aim of this study was to identify potential downstream targets of key oncogenes and TSGs in melanoma (including p14ARF, p16INK4A, BRAF etc). Publications relevant to this series include: Johansson et al. Pigment Cell Res 2007. Keywords: melanoma
2007-03-31 | GSE7127 | GEO
Project description:Loss of function of CDKN2A/B, also known as INK4/ARF [encoding for p16INK4A, p15INK4B, and p14ARF (mouse p19Arf)]), confers susceptibility to cancers, whereas its up-regulation during organismal aging provokes cellular senescence and tissue degenerative disorders. To better understand molecular regulation of the locus, we knocked P2A-mCherry into the C-terminus of p16INK4A, and this construct faithfully recapitulated the endogenous transcription. Using this reporter cell line, we performed a noncoding tiling pooled screening targeting open chromatin regions spanning the approximately 500-kb region in the topological associated domain that includes p16INK4A. In both Cas9- and dCas9-KRAB–mediated screenings, we identified a 42-bp DNA sequence within exon 1β of the ARF gene, as the repressive element controlling p16INK4A expression. Chromatin conformation capture indicated that inactivating this element abolished the physical interaction between p15INK4B and ARF, thereby abolishing p16INK4A repression. This study has revealed a new mechanism of transcriptional regulation of p16INK4A by long-range chromatin interaction.
2019-12-17 | GSE125666 | GEO
Project description:35 Melanoma cell lines hybridized to Affymetrix Hu133_Plus 2 microarrays were analysed for genes differentially expressed between cell lines carrying wild-type p14ARF and those with mutant 14ARF. All of these cell lines contained wild-type p53 (so that the effects of p14ARF mutations could be analysed without contamination from p53). Keywords: Affymetrix Hu133_Plus microarrays
2007-03-31 | GSE7152 | GEO
Project description:Loss of function of CDKN2A/B, also known as INK4/ARF [encoding for p16INK4A, p15INK4B, and p14ARF (mouse p19Arf)]), confers susceptibility to cancers, whereas its up-regulation during organismal aging provokes cellular senescence and tissue degenerative disorders. To better understand molecular regulation of the locus, we knocked P2A-mCherry into the C-terminus of p16INK4A, and this construct faithfully recapitulated the endogenous transcription. Using this reporter cell line, we performed a noncoding tiling pooled screening targeting open chromatin regions spanning the approximately 500-kb region in the topological associated domain that includes p16INK4A. In both Cas9- and dCas9-KRAB–mediated screenings, we identified a 42-bp DNA sequence within exon 1β of the ARF gene, as the repressive element controlling p16INK4A expression. Chromatin conformation capture indicated that inactivating this element abolished the physical interaction between p15INK4B and ARF, thereby abolishing p16INK4A repression. This study has revealed a new mechanism of transcriptional regulation of p16INK4A by long-range chromatin interaction.
2019-12-17 | GSE125841 | GEO
Project description:63 melanoma cell lines hybridized to Affymetrix Hu133_Plus 2 oligo arrays. The aim of this study was to identify potential downstream targets of key oncogenes and TSGs in melanoma (including p14ARF, p16INK4A, BRAF etc). Publications relevant to this series include:; Johansson et al. Pigment Cell Res 2007. Experiment Overall Design: 63 melanoma cell lines hybridized to Affymetrix Hu133_Plus 2 oligo arrays. These cell lines were sequenced for key tumour suppressor genes (TSGs) and oncogenes known to be involved in melanoma development. The microarray data was then analysed together with a particular genotype status (see relevant publications) to identify genes that potentially act downstream of these oncogenes and TSGs to contribute to melanoma development. See publications for analysis methods.
2008-06-15 | E-GEOD-7127 | biostudies-arrayexpress
Project description:Immunotherapy has achieved tremendous success in melanoma. However, only around 50 % of advanced melanoma patients benefit from immunotherapy with immunogenicity of melanomas playing a key role. CDKN2A encoding the two tumor-suppressor proteins p14ARF and p16INK4a belongs to the most frequently inactivated gene loci in advanced melanoma where decreased T cell infiltration is accompanied. While the role of p16INK4a has been aberrantly investigated, knowledge about the function of p14ARF in melanoma therapy is scarce. In this study, we elucidate the impact of reduced p14ARF expression on melanoma immunogenicity. Knockdown of p14ARF in melanoma cell lines diminished the recognition and killing by melanoma differentiation antigen (MDA)-specific T cells. Resistance was caused by a reduction of the peptide surface density of presented MDAs. While antigen presentation via HLA-I molecules was enhanced upon p14ARF downregulation in general, absolute and relative expression of cognate peptides was decreased. Limiting WNT5A signaling reverted this phenotype suggesting an involvement of non-canonical Wnt signaling. Taken together, our data indicate a new mechanism limiting MDA-specific T cell responses by decreasing both absolute and relative MDA-peptide presentation in melanoma.
2023-12-13 | GSE249763 | GEO
Project description:Accumulation of senescent cells with age is believed to be an important driver of aging and age-related diseases. However, the underlying mechanisms and the signaling pathways that regulate senescence remain elusive. In this report, we couple high throughput (HTP) mapping of disease-associated functional SNPs (fSNPs) with proteomics analysis of fSNP-binding regulatory proteins to dissect the CDKN2A/B locus, a locus known to be associated with multiple age-related diseases, as well as overall human longevity. We demonstrate that the homeodomain transcription factor CUX1 specifically binds to a fSNP (rs1537371) associated with atherosclerosis within the CDKN2A/B locus. Although it binds at a considerable distance (> 100 kb), CUX1 is shown to regulate the CDKN2A/B encoded genes p14ARF, p15INK4b, p16INK4a, and ANRIL in endothelial cells (ECs). In-depth analysis demonstrates that endothelial CUX1 expression correlates with telomeric length and is induced by both DNA-damaging agents and oxidative stress. Moreover, induction of CUX1 expression triggers both replicative and stress-induced premature senescence via activating p16INK4A expression. Consistent with these findings, we also detect elevated expression of CUX1 and p16INK4A in the plaques of patients with carotid artery disease. Our HTP strategy therefore identifies CUX1 as a regulator of p16INK4A expression and endothelial senescence and a potential therapeutic target for atherosclerosis and other age-related diseases.
2021-12-05 | GSE186528 | GEO
Project description:p16INK4A inhibits the CDK4/6 kinases and is therefore an important cell cycle regulator. Accumulation of p16INK4A in response to oncogenic transformation leads to cellular senescence and it is therefore frequently lost in cancer. p16INK4A is also known to accumulate under conditions of cellular oxidative stress and therefore could potentially be regulated by redox signaling, which is a form of signal transduction that is mediated by the reversible oxidation of cysteine-thiol side chains in proteins. We found that oxidation of the single cysteine residue in p16INK4A in human cells occurs under relatively mild oxidizing conditions and that this leads to disulfide dependent dimerization. p16INK4A is a well-characterized all alpha-helical protein, but we find that upon cysteine-dependent dimerization, p16INK4A undergoes a dramatic structural rearrangement and forms aggregates that have the typical features of amyloid fibrils, including binding of diagnostic dyes, presence of cross-β sheet structure, and typical dimensions found in electron microscopy. We find that p16INK4A amyloid formation abolishes its function as a CDK4/6 inhibitor in human cells. Taken together, these observations mechanistically link the cellular redox state to the inactivation of p16INK4A through the formation of amyloid fibrils.
2019-09-04 | PXD012353 | Pride