Editors' ChoiceCell Biology

CDK7 stabilizes Yap

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Science Signaling  04 Feb 2020:
Vol. 13, Issue 617, eabb0965
DOI: 10.1126/scisignal.abb0965

CDK7 promotes cell proliferation and tissue growth by protecting the transcriptional coactivator Yap from degradation.

The Hippo signaling pathway restricts cell growth by promoting the cytoplasmic retention of the transcriptional coactivators Yap and Taz. Repression of this kinase cascade enables Yap and Taz to enter the nucleus, where they promote the expression of genes required for cell growth. Cho et al. found that inactivation of cyclin-dependent kinase 7 (CDK7) suppressed eye overgrowth induced by the overexpression of Yorkie (Yki), the Drosophila melanogaster homolog of Yap and Taz. CDK7, together with its cofactors cyclin H and Mat1, promoted the expression of Yki target genes independently of the Hippo kinase cascade and independently of its role as an activator of RNA polymerase II (Pol II), which promotes basal transcription. In the nucleus, CDK7 directly phosphorylated Yki at Ser169, which prevented ubiquitylation of Yki by the E3 ubiquitin ligase complex CRL4DCAF12, thus protecting Yki from degradation. In addition to suppressing Yki-induced tissue overgrowth in flies, knockdown of CDK7 reduced Yap abundance and Yap target gene expression, proliferation, and invasiveness in various cultured human cancer cell lines. Expression of a mutant form of Yap lacking the CDK7 phosphorylation site reversed this suppression more so than did expression of wild-type Yap. In a mouse model of hyperproliferation in the liver, treatment with a pharmacological inhibitor of CDK7 reduced Yap abundance, expression of Yap target genes, hepatocyte proliferation, and overall liver size. These findings not only identify a mechanism by which CDK7 promotes the activity of Yki/Yap but also reveal a potential explanation for why CDK7 promotes the expression of specific sets of target genes in cancer and inflammation rather than only promoting the higher expression of basal transcripts through its stimulation of Pol II activity (see commentary by Piccolo).

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