p53 governs an AT1 differentiation programme in lung cancer suppression

Kaiser, Alyssa M.; Gatto, Alberto; Hanson, Kathryn J.; Zhao, Richard; Raj, Nitin; Ozawa, Michael G.; Seoane, José A.; Bieging-Rolett, Kathryn; Wang, Mengxiong; Li, Irene; Trope, Winston; Liou, Douglas Z.; Shrager, Joseph B.; Plevritis, Sylvia K.; Newman, Aaron M.; Rechem, Capucine Van; Attardi, Laura D.

doi:10.1038/s41586-023-06253-8

Cited by 32 publications

(12 citation statements)

References 73 publications

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“…In addition, because AKT can receive inputs from various signaling pathways other than KGF and YAP/TAZ signaling ( Borok et al., 1998 ; Manning and Toker, 2017 ), AT1 differentiation may be regulated by some specific signals. Activated p53 signaling promotes AT1 cell differentiation, which is beneficial for suppressing lung adenocarcinoma ( Kaiser et al., 2023 ). Activated p53 signaling induces PHLDA3, which represses AKT signaling and induces the apoptosis of cancer cells ( Kawase et al., 2009 ), supporting our finding that AKT inhibition induced AT1 cells alternatively to activated p53 signaling and independently of YAP/TAZ signaling activation.…”

Section: Discussionmentioning

confidence: 99%

“…Among them, the activation of yes-associated protein and the transcriptional coactivator with PDZ-binding motif (YAP/TAZ) signaling is essential for AT1 cell differentiation ( DiGiovanni et al., 2023 ; Gokey et al., 2021 ; LaCanna et al., 2019 ; Liu et al., 2016 ; Nguyen et al., 2021 ; Penkala et al., 2021 ; Warren et al., 2023 ). Other signals such as Notch, transforming growth factor β (TGF-β), Wnt, and p53 are also involved in AT2-to-AT1 cell differentiation ( Finn et al., 2019 ; Frank et al., 2016 ; Kaiser et al., 2023 ; Kanagaki et al., 2021 ; Zhao et al., 2013 ). However, most reports are based on mouse studies and have yet to be validated enough using human alveolar epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

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Screening of factors inducing alveolar type 1 epithelial cells using human pluripotent stem cells

Ohnishi,

Masui,

Suezawa

et al. 2024

Stem Cell Reports

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Screening of factors inducing alveolar type 1 epithelial cells using human pluripotent stem cells

Ohnishi,

Masui,

Suezawa

et al. 2024

Stem Cell Reports

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“…This process occurs at very low rates during homeostasis, with an approximate turnover rate of 0.005% of the alveolar surface with new AT2 cell-derived AT1 cells per day (30). Several signaling pathways have been implicated as regulators of AT2 cell transdifferentiation, including Wnt/β-catenin, BMP, TGF-β, and p53 (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

“…Mice with loss of function of both Sin3a and p53 did not exhibit AT2 cell loss and did not develop significant fibrosis, indicating that activation of the p53 pathway is necessary to induce AT2 cell senescence and fibrosis (24). While some reports suggest that p53 is necessary for complete AT2-to-AT1 cell differentiation in the setting of acute injury, the role of this pathway may be context-and disease-dependent, as ectopic activation can be deleterious (22,32,42).…”

Section: Discussionmentioning

confidence: 99%

Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome

Wang

Michki

Banaschewski

et al. 2023

Preprint

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Hermansky-Pudlak syndrome (HPS) is a genetic disorder of intracellular endosomal trafficking defects associated with pulmonary fibrosis. Double mutant HPS1/2 mice exhibit spontaneous fibrosis and single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity. To identify mechanisms of AT2 cell dysfunction contributing to fibrosis in HPS, we examined lungs from aged HPS1/2 mice and observed regions of AT2 cell loss adjacent to areas of marked AT2 cell hyperplasia as compared to wild type (WT). Overall, there was accelerated loss of AT2 cells in HPS1/2, HPS1, and HPS2 mice with aging based on immunohistochemistry and lineage tracing studies. Lung organoids generated with HPS2 AT2 cells with WT fibroblasts were smaller in size and displayed significantly decreased colony forming efficiency compared to organoids with WT AT2 cells. Utilizing an H1N1 PR8 influenza model to examine AT2 cell regeneration after injury, there was a significant decrease in the percentage of proliferating AT2 cells in HPS1 and HPS2 mice compared to WT mice. RNA sequencing of AT2 cells isolated from unchallenged mice demonstrated upregulation of genes associated with proliferation and cellular senescence in HPS AT2 cells. Collectively, AT2 cells in HPS mice exhibit dysregulated proliferation with transcriptomic features suggesting subpopulations of senescent and hyperproliferative cells. Dysregulated maintenance of the alveolar epithelium with accelerated senescence and aberrant proliferation of AT2 cells appears to be a shared pathway underlying HPS and other sporadic and genetic forms of pulmonary fibrosis.

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“…Following multiple bleomycin‐induced pulmonary fibrosis, elevated cyclin‐dependent kinase inhibitor 1A (P21) in AT2 cells induces cell cycle arrest and damps the differentiation into AT1 cells by disturbing the E1A‐binding protein P300 (P300)–β‐catenin interaction 98 . During the evolution of lung adenocarcinomas (LUADs), single‐cell transcriptomics analyses reveal that P53 promotes AT2 cell differentiation through direct DNA binding, chromatin remodeling, and induction of genes characteristic of AT1 cells, suppressing LUAD 99 …”

Section: Repair and Regeneration Mechanisms Of Alveolar Epithelium Fo...mentioning

confidence: 99%

Repair and regeneration of the alveolar epithelium in lung injury

Wang,

et al. 2024

The FASEB Journal

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Considerable progress has been made in understanding the function of alveolar epithelial cells in a quiescent state and regeneration mechanism after lung injury. Lung injury occurs commonly from severe viral and bacterial infections, inhalation lung injury, and indirect injury sepsis. A series of pathological mechanisms caused by excessive injury, such as apoptosis, autophagy, senescence, and ferroptosis, have been studied. Recovery from lung injury requires the integrity of the alveolar epithelial cell barrier and the realization of gas exchange function. Regeneration mechanisms include the participation of epithelial progenitor cells and various niche cells involving several signaling pathways and proteins. While alveoli are damaged, alveolar type II (AT2) cells proliferate and differentiate into alveolar type I (AT1) cells to repair the damaged alveolar epithelial layer. Alveolar epithelial cells are surrounded by various cells, such as fibroblasts, endothelial cells, and various immune cells, which affect the proliferation and differentiation of AT2 cells through paracrine during alveolar regeneration. Besides, airway epithelial cells also contribute to the repair and regeneration process of alveolar epithelium. In this review, we mainly discuss the participation of epithelial progenitor cells and various niche cells involving several signaling pathways and transcription factors.

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p53 governs an AT1 differentiation programme in lung cancer suppression

Cited by 32 publications

References 73 publications

Screening of factors inducing alveolar type 1 epithelial cells using human pluripotent stem cells

Screening of factors inducing alveolar type 1 epithelial cells using human pluripotent stem cells

Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome

Repair and regeneration of the alveolar epithelium in lung injury

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