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2015 ; 14
(16
): 2619-33
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gab.com Text
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English Wikipedia
Np9, a cellular protein of retroviral ancestry restricted to human, chimpanzee
and gorilla, binds and regulates ubiquitin ligase MDM2
#MMPMID26103464
Heyne K
; Kölsch K
; Bruand M
; Kremmer E
; Grässer FA
; Mayer J
; Roemer K
Cell Cycle
2015[]; 14
(16
): 2619-33
PMID26103464
show ga
Humans and primates are long-lived animals with long reproductive phases. One
factor that appears to contribute to longevity and fertility in humans, as well
as to cancer-free survival, is the transcription factor and tumor suppressor p53,
controlled by its main negative regulator MDM2. However, p53 and MDM2 homologs
are found throughout the metazoan kingdom from Trichoplacidae to Hominidae.
Therefore the question arises, if p53/MDM2 contributes to the shaping of primate
features, then through which mechanisms. Previous findings have indicated that
the appearances of novel p53-regulated genes and wild-type p53 variants during
primate evolution are important in this context. Here, we report on another
mechanism of potential relevance. Human endogenous retrovirus K subgroup HML-2
(HERV-K(HML-2)) type 1 proviral sequences were formed in the genomes of the
predecessors of contemporary Hominoidea and can be identified in the genomes of
Nomascus leucogenys (gibbon) up to Homo sapiens. We previously reported on an
alternative splicing event in HERV-K(HML-2) type 1 proviruses that can give rise
to nuclear protein of 9 kDa (Np9). We document here the evolution of Np9-coding
capacity in human, chimpanzee and gorilla, and show that the C-terminal half of
Np9 binds directly to MDM2, through a domain of MDM2 that is known to be
contacted by various cellular proteins in response to stress. Np9 can inhibit the
MDM2 ubiquitin ligase activity toward p53 in the cell nucleus, and can support
the transactivation of genes by p53. Our findings point to the possibility that
endogenous retrovirus protein Np9 contributes to the regulation of the p53-MDM2
pathway specifically in humans, chimpanzees and gorillas.