LARP7 suppresses P-TEFb activity to inhibit breast cancer progression and metastasis.
Bottom Line: The positive transcription elongation factor b (P-TEFb) stimulates transcriptional elongation by phosphorylating Pol II and antagonizing negative elongation factors.A reservoir of P-TEFb is sequestered in the inactive 7SK snRNP where 7SK snRNA and the La-related protein LARP7 are required for the integrity of this complex.Decreased levels of LARP7 and 7SK snRNA redistribute P-TEFb to the transcriptionally active super elongation complex, resulting in P-TEFb activation and increased transcription of EMT transcription factors, including Slug, FOXC2, ZEB2, and Twist1, to promote breast cancer EMT, invasion, and metastasis.
Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.Show MeSH
Related in: MedlinePlus
Mentions: Because LARP7 is a critical component of the inhibitory 7SK snRNP, we hypothesize that its ability to suppress tumor progression is due to the sequestration of P-TEFb in 7SK snRNP. To test this hypothesis, we first examined the kinase activity of P-TEFb upon LARP7 KD in an in vitro kinase assay using recombinant GST-CTD as a substrate. As predicted, the ability of endogenous CDK9 to phosphorylate the CTD was dramatically higher in the KD cells than in the control cells (Figure 4A).10.7554/eLife.02907.009Figure 4.P-TEFb is required for the increased cell migration and invasion induced by LARP7 KD.
Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.