The RUNX2 transcription factor cooperates with the YES-associated protein, YAP65, to promote cell transformation

Abstract

The Runt box domain DNA-binding transcription factors (RUNX) play key roles in hematopoietic, bone, and gastric development. These factors regulate angiogenesis and tumorigenic events, functioning as either activators or repressors of target genes. Although RUNX2 is an essential bone maturation factor, it has also been found to promote transformation in vivo and cell proliferation in vitro, perhaps by associating with specific coactivators or corepressors. Adenoviral-mediated overexpression of dominant negative RUNX2 or specific reduction of RUNX2 with RNA-interference inhibits cell proliferation. To determine whether RUNX2 also plays a role in cell transformation, RUNX2 interactions with the coactivator Yes-associated protein (YAP65) were examined. RUNX2 associated with YAP65 via a proline-rich segment in the C-terminal domain (PPPY) and coexpression of RUNX2 and YAP65 significantly increased foci formation and anchorage-independent growth relative to each factor alone. However, in contrast to wild-type RUNX2, a mutant RUNX2(P409A), which does not bind YAP65, did not cooperate with YAP65 to promote anchorage-independent growth. RUNX2 is a strong repressor of the cyclin-dependent kinase inhibitor p21(CIP1), which is known to mediate cell transformation. Overexpression of YAP65 prevented RUNX2-dependent downregulation of p21(CIP1) protein expression while promoting cell transformation. The RUNX2(P409A) mutant retained the ability to bind DNA and repress the p21(CIP1) promoter as shown by DNA precipitation and luciferase-reporter assays, respectively, but was not able to relieve repression of the p21(CIP1) promoter. Therefore, these results reveal a novel function of the RUNX2 and YAP65 interaction in oncogenic transformation that may be mediated by modulation of p21(CIP1) protein expression.

Mst2 and Lats Kinases Regulate Apoptotic Function of Yes Kinase-associated Protein (YAP)

“…Similarly, the overexpression of YAP in mammary epithelial cells elicits transformation, perhaps because YAP collaborates in these cells with the amplified myc (51). Simple overexpression of YAP in certain epithelial or fibroblastic cells (HEK293, NIH3T3) does not cause oncogenic transformation, unless additional genes are co-expressed or amplified (32,52). The presence of overexpressed c-myc in systems where YAP caused transformation suggested that for YAP to be oncogenic requires the expression of an additional gene that encodes the anti-apoptotic protein (such as c-Myc, cyclin E, or Runx2).…”

YAP oncogene overexpression supercharges colon cancer proliferation

“…20 YAP tyrosine phosphorylation, putatively by Src family kinases, also enables YAP binding to Runx2, resulting in suppression of Runx2 transcriptional activity toward p21 cdki 21 while promoting transformation. 22 Thus, YAP is capable of being regulated by diverse upstream inputs that appear to elicit distinct and even opposing outputs, e.g., as an oncogene 23 or a tumor suppressor. 24 What then are YAP's physiologic functions in various contexts; what are the relevant upstream inputs, and by what mechanisms are each of these functions regulated?…”

The Role and Clinical Significance of Yes-Associated Protein 1 in Human Osteosarcoma

“…Importantly, YAP, a mediator of Hippo signaling, interacts with the native RUNX2 protein and suppresses RUNX2 transcriptional activity in a dose-dependent manner. Inhibition of the Yes kinase dissociates endogenous Runx2-YAP complexes (22)(23)(24). Moreover, the RUNX2 transcription factor cooperates with YAP65 to promote oncogenic transformation (25).…”