Research ArticleCell Biology

Cardiac hypertrophy induced by active Raf depends on Yorkie-mediated transcription

See allHide authors and affiliations

Sci. Signal.  03 Feb 2015:
Vol. 8, Issue 362, pp. ra13
DOI: 10.1126/scisignal.2005719

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Growing fly hearts

Organ size arises from both the number of cells and the size of the cells in the organ. The Hippo-Yorkie pathway regulates the growth of many organs, including the heart. In mice, expression of activated Yorkie orthologs promotes cardiac hyperplasia. Moreover, some patients with Noonan syndrome, which is associated with enlarged hearts, have activating mutations in Raf, which is a kinase involved in stimulating cell proliferation or an increase in cell size. Yu et al. examined the mechanism by which activated Raf promotes cardiac hypertrophy in the fruit fly Drosophila melanogaster. Knockdown of Yorkie inhibited hypertrophy induced by Raf. In contrast to mice, expression of activated Yorkie in the fly induced cardiac hypertrophy, but not hyperplasia, which was inhibited by knockdown of the Yorkie-associated transcription factor Scalloped. Overexpression of the Scalloped-associated corepressor Tgi inhibited hypertrophy induced by activated Raf or activated Yorkie and inhibited the ability of Raf and Yorkie to stimulate Scalloped-dependent transcription in cultured cells. These results lead to the question of whether Raf can also stimulate Yorkie in cardiac hypertrophy by promoting cell growth rather than proliferation in mammals.

Abstract

Organ hypertrophy can result from enlargement of individual cells or from cell proliferation or both. Activating mutations in the serine-threonine kinase Raf cause cardiac hypertrophy and contribute to Noonan syndrome in humans. Cardiac-specific expression of activated Raf also causes hypertrophy in Drosophila melanogaster. We found that Yorkie (Yki), a transcriptional coactivator in the Hippo pathway that regulates organ size, is required for Raf-induced cardiac hypertrophy in flies. Although aberrant activation of Yki orthologs stimulates cardiac hyperplasia in mice, cardiac-specific expression of an activated mutant form of Yki in fruit flies caused cardiac hypertrophy without hyperplasia. Knockdown of Yki caused cardiac dilation without loss of cardiomyocytes and prevented Raf-induced cardiac hypertrophy. In flies, Yki-induced cardiac hypertrophy required the TEA domain–containing transcription factor Scalloped, and, in mammalian cells, expression of mouse RafL613V, an activated form of Raf with a Noonan syndrome mutation, increased Yki-induced Scalloped activity. Furthermore, overexpression of Tgi (a Tondu domain–containing Scalloped-binding corepressor) in the fly heart abrogated Yki- or Raf-induced cardiac hypertrophy. Thus, crosstalk between Raf and Yki occurs in the heart and can influence Raf-mediated cardiac hypertrophy.

View Full Text