Sarkar Aradhan, Iwasa Hiroaki, Hossain Shakhawoat, Xu Xiaoyin, Sawada Takeru, Shimizu Takanobu, Maruyama Junichi, Arimoto-Matsuzaki Kyoko, Hata Yutaka
Department of Medical Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.
Department of Biochemistry and Molecular Biology, University of Rajshahi, Bangladesh.
FEBS Lett. 2017 Jan;591(2):260-272. doi: 10.1002/1873-3468.12551. Epub 2017 Jan 17.
The tumor suppressor Ras-association domain family member 6 (RASSF6) has Ras-association domain (RA) and Salvador/RASSF/Hippo domain (SARAH). RASSF6 antagonizes MDM2, stabilizes p53, and induces apoptosis and cell cycle arrest. We previously demonstrated the interaction between RASSF6 and MDM2, but did not determine how both proteins interact with each other. We have shown here that N-terminal, RA, and SARAH domains of RASSF6 interact with MDM2 at distinct regions. RA binds to the RING-finger region of MDM2 and stabilizes p53. SARAH binds RA and blocks the interaction between RA and MDM2. RA overexpression induces p53-dependent apoptosis and senescence. In the presence of active KRas, the interaction between RA and MDM2 is recovered. In this way, RA and SARAH play an important role in Ras-mediated regulation of p53.
肿瘤抑制因子Ras关联结构域家族成员6（RASSF6）具有Ras关联结构域（RA）和Salvador/RASSF/Hippo结构域（SARAH）。RASSF6拮抗MDM2，稳定p53，并诱导细胞凋亡和细胞周期停滞。我们之前证明了RASSF6与MDM2之间的相互作用，但未确定这两种蛋白如何相互作用。我们在此表明，RASSF6的N端、RA和SARAH结构域在不同区域与MDM2相互作用。RA与MDM2的环指区域结合并稳定p53。SARAH与RA结合并阻断RA与MDM2之间的相互作用。RA过表达诱导p53依赖的细胞凋亡和衰老。在活性KRas存在的情况下，RA与MDM2之间的相互作用得以恢复。通过这种方式，RA和SARAH在Ras介导的p53调节中发挥重要作用。
