Cooperative role of RanBP9 and P73 in mitochondria-mediated apoptosis

Abstract

Mitochondrial dysfunction and synaptic damage are critical early features of Alzheimer's disease (AD) associated with amyloid b (Ab) and s. We previously reported that the scaffolding protein RanBP9, which is overall increased in AD, simultaneously promotes Ab generation and focal adhesion disruption by accelerating the endocytosis of APP and b1-integrin, respectively. Moreover, RanBP9 induces neurodegeneration in vitro and in vivo and mediates Ab-induced neurotoxicity. However, little is known regarding the mechanisms underlying such neurotoxic processes. Here, we show that RanBP9 induces the loss of mitochondrial membrane potential and increase in mitochondrial superoxides associated with decrease in Bcl-2, increase in Bax protein and oligomerization, fragmentation of mitochondria, and cytochrome c release. RanBP9-induced neurotoxic changes are significantly prevented by the mitochondrial fission inhibitor Mdivi-1 and by classical inhibitors of the mitochondrial apoptosis, XIAP, Bcl-2, and Bcl-xl. RanBP9 physically interacts with the tumor suppressor p73 and increases endogenous p73a levels at both transcriptional and post-translational levels;moreover, the knockdown of endogenous p73 by siRNA effectively blocks RanBP9 and Ab1-42-induced mitochondria-mediated cell death. Conversely, siRNA knockdown of endogenous RanBP9 also suppresses p73-induced apoptosis, suggesting that RanBP9 and p73 have cooperative roles in inducing cell death. Taken together, these finding implicate the RanBP9/p73 complex in mitochondria-mediated apoptosis in addition to its role in enhancing Ab generation. The accumulations of amyloid b (Ab) peptide and hyperphosphorylated t are the major pathological hallmarks of Alzheimer's disease (AD). Mounting evidence clearly indicates that mitochondrial dysfunction is a critical early component of AD and related neurodegenerative disorders.

Cell signalling pathway regulation by RanBPM: molecular insights and disease implications

“…Stable RanBPM downregulated cells showed increased protein levels of anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-X L and, following IR treatment, decreased mitochondrial localization of Bax, a pro-apoptotic Bcl-2 family member responsible for mitochondrial permeabilization and cytochrome-c release, a central step in the activation of apoptosis through the intrinsic pathway [5,86]. A later study confirmed that overexpression of RanBPM resulted in decreased Bcl-2 protein levels and increased Bax oligomerization [87]. This study also demonstrated that cells overexpressing RanBPM had increased mitochondrial membrane permeability and increased cytoplasmic cytochrome-c compared with control cells, demonstrating that RanBPM overexpression induces mitochondrial membrane depolarization resulting in the activation of apoptosis.…”

A balancing act: orchestrating amino-truncated and full-length p73 variants as decisive factors in cancer progression

“…RanBP9 stabilizes p73 at the transcriptional and posttranslational level via physical interaction. 41 Furthermore, the ability to stimulate expression of the death receptors CD95, tumor necrosis factor (TNF)-R1, TRAIL-R1 and TRAIL-R2 as well as the caspases-3, -6 and -8 suggests that p73 is also involved in the extrinsic apoptosis pathway. 10,12 Induction of p73-dependent programmed cell death following DNA damage also involves endoplasmic reticulum stress and upregulation of scotin, a putative transmembrane protein able to colocalize with endoplasmic reticulum heat-shock proteins, such as GRP94.…”

Insights from the computational analysis of CD271 glycation in mescenchymal stem cells in diabetes mellitus as a predisposition to latent tuberculosis

“…KIDINS220 interacts with RanBP9, a molecule critical for functioning of death domain [14]. RanBP9 is proved to be a pro-apoptotic protein in other cells as well [15]. …”