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Cryptochrome deletion in p53 mutant mice enhances apoptotic and anti-tumorigenic responses to UV damage at the transcriptome level

ABSTRACT: Previous studies have demonstrated that deletion of Cryptochromes (CRY) protects p53-/- mutant mice from early onset of cancer and extends their median lifespan by about 1.5 fold. In vitro studies had revealed that deletion of CRY enhances apoptosis in response to UV damage through activation of p73, and inactivation of GSK3β. However, it was not known at the transcriptome-wide level how CRY deletion delays the onset of cancer in p53-/- mutant mice. In this study, an RNA-seq approach was taken to identify the differentially regulated genes and pathways in p53-/- and p53-/-Cry1-/-Cry2-/- mouse embryonic fibroblasts following UV-induced DNA damage. Gene Set Enrichment Analysis demonstrated that immune surveillance associated genes regulated by IFN-γ showed increased responses, as well as genes involved in TNFα signaling via NF-κB. Protein network analysis helped identify key genes such as p21, Egr3, Sirt1, Jun and Casp1 among differentially regulated genes, and revealed their interaction partners. Collectively, the present study suggests that additional genes involved in NF-κB regulation, IFN-γ response, as well as non-coding RNAs may contribute to delaying the onset of cancer in p53-/-Cry1-/-Cry2-/- mice compared to p53-/- mutant mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE115102 | GEO | 2018/10/01

REPOSITORIES: GEO

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Project description:Plant growth and development are strongly affected by light signals perceived by phytochromes (phy) and cryptochromes (cry). The physical interaction between photoreceptors and the cross-talk among downstream signalling steps creates a network of interactions in which the action of one photoreceptor depends on the status of the others. The processes modulated by phy and or cry include seed germination, seedling de-etiolation, plant body formation and flowering. Compared to the wild type the leaves of the phyB mutant are characterised by their extended petioles and pale colour. These features resemble the phenotype of normal plants grown under the low red to far-red ratios typical of dense plant canopies thus providing support to the idea that phyB plays a key role in the perception of high red to far-red ratios. The triple mutant lacking phyA cry1 and cry2 shows little differences in leaf size and shape with the wild typebut the quadruple phyA phyB cry1 cry2 mutant shows severely impaired leaf expansion. In addition to the specific effects on leaf sizeshape and pigmentation the phyB mutation accelerates flowering in the wild type background. This effect can be observed as a reduced number of days between sowing and visible flower buds (time scale) and as a reduced final number of leaves (developmental scale). However in the phyA cry1 cry2 triple mutant background the phyB mutation accelerates flowering on a developmental scale but severely delays flowering on a time scale. The long photoperiods inducing flowering are perceived by the leaves. Flowering signals that could include hormones and sugars migrate from the leaves to the apex in response to the light stimulus. We propose to compare the following mRNA samples of expanding leaves: 1) wild type 2) phyB mutant 3) phyA cry1 cry2 triple mutant 4) phyA phyB cry1 cry2 quadruple mutant. The comparison between the wild type and the phyB mutant will help to uncover the changes in leaf mRNA patterns underlying enhanced petiole growthreduced pigmentation and early flowering in response to the absence of phyB activity. The comparison between the phyA cry1 cry2 triple mutant and the phyA phyB cry1 cry2 quadruple mutant should reveal the mRNA differences between photosynthetic leaves with dramatically different abilities to expand. The added value of the simultaneous analysis of the two comparisons is that effect of phyB is different in both genetic backgrounds and this should provide information on the mechanisms and significance of photoreceptor interactions.

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Cryptochrome deletion in p53 mutant mice enhances apoptotic and anti-tumorigenic responses to UV damage at the transcriptome level

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