A Regulatory Mechanism Involving TBP-1/Tat-Binding Protein 1 and Akt/PKB in the Control of Cell Proliferation

Y-box binding protein 1 (YBX-1 or YB-1) is an oncoprotein that promotes replicative immortality, tumor cell invasion and metastasis. The increase in the abundance of YB-1 in the cell or YB-1 translocation from the cytoplasm to the nucleus is characteristic of malignant cell growth. We have previously reported that DNp63a, a transcription factor that is known to play a pivotal role in keratinocyte proliferation and differentiation, promotes YB-1 nuclear accumulation. Here, we show that YB-1 is highly expressed in proliferating keratinocytes and is down-regulated during keratinocyte differentiation. DNp63a reduces YB-1 protein turnover and leads to accumulation of ubiquitin-conjugated YB-1 into the nucleus. Reduction of YB-1 protein level, following treatment with a DNA-damaging agent, is inhibited by DNp63a suggesting that YB-1 and DNp63a interplay can support keratinocyte proliferation and protect cells from apoptosis under genotoxic stress.

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“…MG132 treatment was carried out as previously described (Sepe et al . ). TPT (topotecan) was purchased from Glaxo Smith‐Kline (Verona, Italy).…”

Section: Methodsmentioning

confidence: 97%

ΔNp63α controls YB‐1 protein stability: evidence on YB‐1 as a new player in keratinocyte differentiation

et al. 2016

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“…A knockdown of PSMC3 in human immortalized fibroblasts increased cell proliferation. 130 CELF1 has been associated with Alzheimer disease and obesity. 131 Consequently, MTCH2 SNVs regulate gene expression of other cis-genes related to obesity, food intake, and/or cell number.…”

Section: Mt-ndna Candidate Genes Associations (Adipose Traits)mentioning

confidence: 99%

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Kraja¹,

Liu

Fetterman

et al. 2019

The American Journal of Human Genetics

113

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Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNAþ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p % 5EÀ04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p % 1EÀ03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p % 1EÀ06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis-and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

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“…pcDNAARFT8A and T8D plasmids were described in [ 11 ]. pCMVMDM2 wt, pCMVMDM2 1–441 , pCMVMDM2Δ 150–230 were described in [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

MDM2-Mediated Degradation of p14ARF: A Novel Mechanism to Control ARF Levels in Cancer Cells

et al. 2015

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We here show a new relationship between the human p14ARF oncosuppressor and the MDM2 oncoprotein. MDM2 overexpression in various cancer cell lines causes p14ARF reduction inducing its degradation through the proteasome. The effect does not require the ubiquitin ligase activity of MDM2 and preferentially occurs in the cytoplasm. Interestingly, treatment with inhibitors of the PKC (Protein Kinase C) pathway and use of p14ARF phosphorylation mutants indicate that ARF phosphorylation could play a role in MDM2 mediated ARF degradation reinforcing our previous observations that ARF phosphorylation influences its stability and biological activity. Our study uncovers a new potentially important mechanism through which ARF and MDM2 can counterbalance each other during the tumorigenic process.

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A Regulatory Mechanism Involving TBP-1/Tat-Binding Protein 1 and Akt/PKB in the Control of Cell Proliferation

Cited by 7 publications

References 37 publications

ΔNp63α controls YB‐1 protein stability: evidence on YB‐1 as a new player in keratinocyte differentiation

ΔNp63α controls YB‐1 protein stability: evidence on YB‐1 as a new player in keratinocyte differentiation

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

MDM2-Mediated Degradation of p14ARF: A Novel Mechanism to Control ARF Levels in Cancer Cells

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