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Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation (2)

ABSTRACT: Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation (2)

PROVIDER: PRJNA612542 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11306086.fastq.gz	Fastqsanger.gz
	SRR11306087.fastq.gz	Fastqsanger.gz
	SRR11306088.fastq.gz	Fastqsanger.gz
	SRR11306089.fastq.gz	Fastqsanger.gz
	SRR11306090.fastq.gz	Fastqsanger.gz

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Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation (2)

Project description:In this study we examine the outcomes of p16INK4a activation in the adult epidermis. We found that prolonged expression of p16INK4a induces epidermal hyperplasia and dysplasia. We also found that continued p16INK4a expression increased the number of epidermal papillomas that developed after carcinogen treatment. Profling of p16INK4a- expressing cells showed elevated levels of Wnt-pathway ligands and targets, and pharmacologic or genetic Wnt inhibition suppressed p16-induced hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16-expressing cells are typically found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that in addition to its cell-autonomous role in blocking cell proliferation, p16 can induce hyperplasia through paracrine stimulation, suggesting that its activity contributes to the formation of early premalignant epidermal lesions.

2020-04-06 | GSE146978 | GEO

Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation (1)

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Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation

Project description:Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation

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Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation (1)

Project description:Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation (1)

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Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-04-06 | GSE146979 | GEO

Chronic expression of p16<sup>INK4a</sup> in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation.

Project description:p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.

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Nucleophosmin supports WNT-driven hyperproliferation and tumour initiation

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Nucleophosmin sustains WNT-driven cell proliferation and tumour initiation in vivo

Project description:Nucleophosmin (NPM1) is a nucleolar protein frequently mutated in haematopoietic malignancies and overexpressed in many solid tumours, but little is known about its functional role in carcinogenesis. Here, we identify NPM1 as a commonly upregulated gene following APC loss in tissues that positively respond to high WNT signalling. High NPM1 expression correlates with increased proliferation in patients with colorectal cancer (CRC). We show that whilst dispensable for adult epithelial tissue homeostasis, NPM1 loss has a profound effect on WNT-driven intestinal and liver tumourigenesis, leading to reduced proliferation and extension of survival. Mechanistically, NPM1 depletion triggers integrated stress response (ISR) and p53 pathway activation. Genetically or chemically blunting these pathways, rescues proliferation following NPM1 loss. Overall, our results demonstrate that NPM1 supports WNT-driven cell proliferation and tumour initiation by attenuating induction of ISR and p53 pathway activation. Being dispensable for homeostasis, NPM1 presents itself as a promising target for cancer therapy in WNT-driven tumours with functional p53, including treatment-refractory KRAS-mutant CRC and hepatic cancers.

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Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A

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

equinox is a planarian wound epidermis gene required for the initiation of regeneration

Project description:equinox is a planarian wound epidermis gene required for the initiation of regeneration

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