Nurr1 is a member of the NGFI-B nuclear orphan receptor family which includes two other members, Nur77 and Nor-1. Nurr1 is essential for the development and survival of dopaminergic neurons. It was reported that Nurr1 has antiapoptotic functions, however, the mechanisms by which Nurr1 mediates these effects remain unknown. Here, we show that overexpression of Nurr1 decreases Bax expression whereas knockdown of Nurr1 increases Bax expression. Nurr1 also interacts with p53 and represses its assembly. Furthermore, Nurr1 represses p53 transcriptional activity in interaction-dependent and dose-dependent manners. Moreover, Nurr1 protects cells from doxorubicin-induced apoptosis. These findings provide evidence that Nurr1 promotes cell survival through its interacting with and repressing p53, thus implicating that Nurr1 may play an important role in carcinogenesis and other diseases. (Mol Cancer Res 2009;7(8):1408-15)

Compelling evidence has revealed that biased activation of G protein-coupled receptor (GPCR) signaling, including angiotensin II (AngII) receptor type 1 (AT1) signaling, plays pivotal roles in vascular homeostasis and injury, but whether a clinically relevant endogenous biased antagonism of AT1 signaling exists under physiological and pathophysiological conditions has not been clearly elucidated. Here, we show that an extracellular matrix protein, cartilage oligomeric matrix protein (COMP), acts as an endogenous allosteric biased modulator of the AT1 receptor and its deficiency is clinically associated with abdominal aortic aneurysm (AAA) development. COMP directly interacts with the extracellular N-terminus of the AT1 via its EGF domain and inhibits AT1-β-arrestin-2 signaling, but not Gq or Gi signaling, in a selective manner through allosteric regulation of AT1 intracellular conformational states. COMP deficiency results in activation of AT1a-β-arrestin-2 signaling and subsequent exclusive AAA formation in response to AngII infusion. AAAs in COMP–/– or ApoE–/– mice are rescued by AT1a or β-arrestin-2 deficiency, or the application of a peptidomimetic mimicking the AT1-binding motif of COMP. Explorations of the endogenous biased antagonism of AT1 receptor or other GPCRs may reveal novel therapeutic strategies for cardiovascular diseases.

No abstract