DNA replication in progenitor cells and epithelial regeneration after lung injury requires the oncoprotein MDM2

Singh, S. K.; Vaughan, Catherine; Rabender, Christopher S.; Mikkelsen, Ross B.; Deb, Sumitra

doi:10.1172/jci.insight.128194

Cited by 11 publications

(9 citation statements)

References 60 publications

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“…Additionally, MDM2, a gene regulated by AKT expression that regulates apoptosis, showed similar kinetics and further demonstrates how AKT-reliant genes persist within the FAK-inhibited fibroblast subset (Supplementary Fig. 4c) 67 . RNA velocity analysis also revealed an enrichment of pre-mRNA for PIEZO1 and CAPZA2 in FAK-inhibited cells.…”

Section: Mechanotransduction Inhibition Induces Regenerative Programsmentioning

confidence: 54%

Disrupting biological sensors of force promotes tissue regeneration in large organisms

et al. 2021

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Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mechanical properties. How these adaptations may affect tissue injury has not been previously examined in large animals and humans. Here, we show that blocking mechanotransduction signaling through the focal adhesion kinase pathway in large animals significantly accelerates wound healing and enhances regeneration of skin with secondary structures such as hair follicles. In human cells, we demonstrate that mechanical forces shift fibroblasts toward pro-fibrotic phenotypes driven by ERK-YAP activation, leading to myofibroblast differentiation and excessive collagen production. Disruption of mechanical signaling specifically abrogates these responses and instead promotes regenerative fibroblast clusters characterized by AKT-EGR1.

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Section: Mechanotransduction Inhibition Induces Regenerative Programsmentioning

confidence: 54%

Disrupting biological sensors of force promotes tissue regeneration in large organisms

et al. 2021

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“…Immunohistochemistry. Staining was performed on formalin-fixed paraffin embedded lung tissue specimens as described 72 . Tissue embedding and sectioning was performed by the VCU Macromolecule Core laboratory.…”

Section: Discussionmentioning

confidence: 99%

The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3

et al. 2021

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Abstractp53 mutations with single amino acid changes in cancer often lead to dominant oncogenic changes. Here, we have developed a mouse model of gain-of-function (GOF) p53-driven lung cancer utilizing conditionally active LSL p53-R172H and LSL K-Ras-G12D knock-in alleles that can be activated by Cre in lung club cells. Mutation of the p53 transactivation domain (TAD) (p53-L25Q/W26S/R172H) eliminating significant transactivation activity resulted in loss of tumorigenicity, demonstrating that transactivation mediated by or dependent on TAD is required for oncogenicity by GOF p53. GOF p53 TAD mutations significantly reduce phosphorylation of nearby p53 serine 20 (S20), which is a target for PLK3 phosphorylation. Knocking out PLK3 attenuated S20 phosphorylation along with transactivation and oncogenicity by GOF p53, indicating that GOF p53 exploits PLK3 to trigger its transactivation capability and exert oncogenic functions. Our data show a mechanistic involvement of PLK3 in mutant p53 pathway of oncogenesis.

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“…Outside of the kidney, MDM2 activates Notch1 signaling in lung club and alveolar cells and induces DNA replication and proliferation in lung progenitor cells in response to chemical-or radiation-induced injury (Singh et al 2019). These varied findings suggest that MDM2 may have a wide range of effects on Notch1 signaling and physiological activity, depending on disease, organ, and cell type.…”

Section: Mdm2 and Notchmentioning

confidence: 99%

The roles and regulation of MDM2 and MDMX: it is not just about p53

et al. 2021

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Most well studied as proteins that restrain the p53 tumor suppressor protein, MDM2 and MDMX have rich lives outside of their relationship to p53. There is much to learn about how these two proteins are regulated and how they can function in cells that lack p53. Regulation of MDM2 and MDMX, which takes place at the level of transcription, post-transcription, and protein modification, can be very intricate and is context-dependent. Equally complex are the myriad roles that these two proteins play in cells that lack wild-type p53; while many of these independent outcomes are consistent with oncogenic transformation, in some settings their functions could also be tumor suppressive. Since numerous small molecules that affect MDM2 and MDMX have been developed for therapeutic outcomes, most if not all designed to prevent their restraint of p53, it will be essential to understand how these diverse molecules might affect the p53-independent activities of MDM2 and MDMX.

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DNA replication in progenitor cells and epithelial regeneration after lung injury requires the oncoprotein MDM2

Cited by 11 publications

References 60 publications

Disrupting biological sensors of force promotes tissue regeneration in large organisms

Disrupting biological sensors of force promotes tissue regeneration in large organisms

The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3

The roles and regulation of MDM2 and MDMX: it is not just about p53

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