Aurora-A phosphorylates hnRNPK and disrupts its interaction with p53

Abstract

a b s t r a c tAmplification of Aurora-A, encoding a cell cycle-regulating kinase, has been reported in human cancers. Although Aurora-A is known to directly phosphorylate and down-regulate p53, the detailed mechanism remains unclear. Here we show that Aurora-A phosphorylates hnRNPK, a transcriptional coactivator of p53, on serine 379. This phosphorylation does not affect the post-transcriptional activity or cellular localization of hnRNPK, but disrupts its interaction with p53. Inverse correlation between Aurora-A activity and hnRNPK-p53 interaction was further demonstrated in DNA-damaged cells. Our results provide an alternative mechanism, whereby via phosphorylating hnRNPK Aurora-A participates in regulating p53 activity during DNA damage. Structured summary of protein interactions:Aurora-A physically interacts with hnRNPK by anti tag coimmunoprecipitation (View interaction) p53 physically interacts with hnRNPK by pull down (View interaction) p53 physically interacts with hnRNPK by anti bait coimmunoprecipitation (View interaction) hnRNPK physically interacts with p53 by anti bait coimmunoprecipitation (View interaction) Aurora-A phosphorylates hnRNPK by protein kinase assay (View interaction) hnRNPK physically interacts with Aurora-A by anti bait coimmunoprecipitation (View interaction)

Transcription factors expressed in embryonic and adult olfactory bulb neural stem cells reveal distinct proliferation, differentiation and epigenetic control

“…In passage 6 proliferating OBNSCs, eleven TF genes were up-regulated (fold change ≤ 6-30). The expression of FOXO4, CTNNB1, NFIC, TGIF1, GTF2H4, TSHZ1, HNRNPAB, FOXN2, ZFP36L2, HNRNPK, and TAF12 were up-regulated by 30 (Fig. 3, Tables S1, S2).…”

“…Phosphorylation of HNRNPK by Aurora-A (AURKA) disrupts its interaction with p53. Inverse correlation between Aurora-A (AURKA) activity and HNRNPK-p53 interaction was demonstrated in DNA-damaged cells [30]. Among the 28 TF genes that were up-regulated (fold change ≤2.13-39.1) (Fig.…”

Aurora kinases: novel therapy targets in cancers

“…Interestingly, AURKA also inhibits p53 activity via phosphorylating heterogeneous nuclear ribonucleoprotein K (hnRNPK) on Ser379, a transcriptional coactivator of p53 required for p53 activation in the occurrence of gene damage [93]. Similarly, AURKB can suppress p53 transcriptional activity through forming complex with novel inhibitor of histone acetyltransferase repressor (NIR) and p53, in which NIR functions as a scaffold protein to mediate AURKB localization to the DNA binding domain (DBD) of p53 and then phosphorylates p53 on Ser269 and Thr284 in DBD.…”

Functional Significance of Aurora Kinases–p53 Protein Family Interactions in Cancer

“…The RNA-binding protein, such as hnRNPK, is a p53 transcriptional cofactor that promotes gene expression in response to DNA damage and is also a target of MDM2 (13, 14). While Aurora-A-mediated hnRNPK phosphorylation at serine 379 disrupts its interaction with p53 and impairs DNA damage-induced gene expression, MDM2 phosphorylation at serine 166 enhances its protein stability and in turn destabilizes p53 (15–17). These findings demonstrate that Aurora-A is involved in regulating p53 downstream signaling negatively affecting growth arrest and apoptotic response pathways.…”