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Shaping the regulat...
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Karakostis, Konstantinos
(författare)
Shaping the regulation of the p53 mRNA tumour suppressor : the co-evolution of genetic signatures
- Artikel/kapitelEngelska2019
Förlag, utgivningsår, omfång ...
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2019-09-13
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BioMed Central,2019
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electronicrdacarrier
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LIBRIS-ID:oai:DiVA.org:umu-164405
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https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-164405URI
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https://doi.org/10.1186/s12885-019-6118-yDOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:for swepub-publicationtype
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Structured RNA regulatory motifs exist from the prebiotic stages of the RNA world to the more complex eukaryotic systems. In cases where a functional RNA structure is within the coding sequence a selective pressure drives a parallel co-evolution of the RNA structure and the encoded peptide domain. The p53-MDM2 axis, describing the interactions between the p53 tumor suppressor and the MDM2 E3 ubiquitin ligase, serves as particularly useful model revealing how secondary RNA structures have co-evolved along with corresponding interacting protein motifs, thus having an impact on protein - RNA and protein - protein interactions; and how such structures developed signal-dependent regulation in mammalian systems. The p53(BOX-I) RNA sequence binds the C-terminus of MDM2 and controls p53 synthesis while the encoded peptide domain binds MDM2 and controls p53 degradation. The BOX-I peptide domain is also located within p53 transcription activation domain. The folding of the p53 mRNA structure has evolved from temperature-regulated in pre-vertebrates to an ATM kinase signal-dependent pathway in mammalian cells. The protein - protein interaction evolved in vertebrates and became regulated by the same signaling pathway. At the same time the protein - RNA and protein - protein interactions evolved, the p53 trans-activation domain progressed to become integrated into a range of cellular pathways. We discuss how a single synonymous mutation in the BOX-1, the p53(L22 L), observed in a chronic lymphocyte leukaemia patient, prevents the activation of p53 following DNA damage. The concepts analysed and discussed in this review may serve as a conceptual mechanistic paradigm of the co-evolution and function of molecules having roles in cellular regulation, or the aetiology of genetic diseases and how synonymous mutations can affect the encoded protein.
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Fåhraeus, RobinUmeå universitet,Patologi,Université Paris 7, INSERM UMR 1131, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.(Swepub:umu)rofa0013
(författare)
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Umeå universitetPatologi
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:BMC Cancer: BioMed Central19:11471-2407
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