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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)

2020-04-06 | GSE121728 | GEO

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

| PRJNA612540 | ENA

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)

| PRJNA498273 | ENA

Chronic expression of p16INK4a 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.

| S-EPMC7264228 | biostudies-literature

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

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

Genotoxicity induces epithelial hyperplasia and lineage infidelity via fibroblast IL-1β

Project description:Epithelial tissues possess a barrier function that must be restored following injury. Repair often involves changes in cell fate, but it remains poorly understood how cell plasticity is induced and whether responses vary with distinct types of damage. Here, we reveal that genotoxic agents, but not mechanical damage, induce hyperplasia and lineage infidelity in the interfollicular epidermis, as well as in two epidermal subappendages: the mammary gland and hair follicle. DNA damage to the epidermis promotes stromal proliferation, and induces basal cell hyperplasia with formation of abnormal, multi-layered K14+/K10+ cells. Unexpectedly, this behavior is epithelial cell non-autonomous, but independent of immunity. Instead, dermal fibroblasts are both necessary and sufficient to induce the epithelial response. We identify a previously unrecognized fibroblast-specific NLRP3 inflammasome that drives this response via IL-1β. Thus, genotoxic agents, used chemotherapeutically to promote cancer cell death, can have the opposite effect on wild-type epithelia, paradoxically promoting hyperplasia and inducing both stemness and lineage infidelity via a non-autonomous, fibroblast-driven mechanism.

2020-12-16 | GSE139272 | GEO

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

| PRJNA743075 | ENA

WNT ligands control initiation and progression of human papilloma-virus-driven squamous cell carcinoma

Project description:Human papilloma virus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT-signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT-ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/b-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT-secretion may thus represent a promising approach for therapeutic intervention.

2018-12-13 | GSE108454 | GEO

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