Abstract
Mst1 is a central Ser-Thr kinase in the Hippo pathway, which promotes apoptosis and inhibits cell proliferation. We have shown previously that, in cardiomyocytes, oxidative stress activates Mst1 at mitochondria, where Mst1 phosphorylates Bcl-xL at Ser14, inducing dissociation of Bcl-xL from Bax and thereby promoting apoptosis. However, the functional significance of Ser14 phosphorylation of endogenous Bcl-xL in vivo remains elusive. We generated knockin (KI) mice in which Ser14 of Bcl-xL is replaced with Ala. KI mice were born at the expected Mendelian ratio, and adult KI mice exhibited normal cardiac morphology and function at baseline. However, KI mice were protected from myocardial ischemia/reperfusion (I/R) injury and exhibited reduced cardiomyocyte apoptosis. Although suppression of endogenous Mst1 also reduced I/R injury, there was no additive protective effect when Mst1 was inhibited in KI mice. The development of dilated cardiomyopathy induced by cardiac-specific overexpression of Mst1 was also ameliorated in KI mice. Lats2 and YAP, two other key components of the Hippo pathway, were not affected in KI mice. These results suggest that Ser14 phosphorylation of Bcl-xL plays an essential role in mediating both cardiomyocyte apoptosis and myocardial injury by acting as a key downstream mediator of Mst1 independently of the canonical Hippo pathway.
Authors
Michinari Nakamura, Peiyong Zhai, Dominic P. Del Re, Yasuhiro Maejima, Junichi Sadoshima
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.
