RanBPM Has Proapoptotic Activities That Regulate Cell Death Pathways in Response to DNA Damage

Abstract

Ran-binding protein M (RanBPM) is a nucleocytoplasmic protein previously implicated in various signaling pathways, but whose function remains enigmatic. Here, we provide evidence that RanBPM functions as an activator of apoptotic pathways induced by DNA damage. First, transient expression of RanBPM in HeLa cells induced cell death through caspase activation, and in the long-term, forced expression of RanBPM impaired cell viability. RanBPM COOH-terminal domain stimulated the ability of RanBPM to induce caspase activation, whereas this activity was negatively regulated by the central SPRY domain. Second, small interfering RNA-directed knockdown of RanBPM prevented DNA damage-induced apoptosis, as evidenced by the marked reduction in caspase-3 and caspase-2 activation. This correlated with a magnitude fold increase in the survival of RanBPM-depleted cells. Following ionizing radiation treatment, we observed a progressive relocalization of RanBPM from the nucleus to the cytoplasm, suggesting that the activation of apoptotic pathways by RanBPM in response to ionizing radiation may be regulated by nucleocytoplasmic trafficking. Finally, RanBPM downregulation was associated with a marked decrease of mitochondria-associated Bax, whereas Bcl-2 overall levels were dramatically upregulated. Overall, our results reveal a novel proapoptotic function for RanBPM in DNA damage-induced apoptosis through the regulation of factors involved in the mitochondrial apoptotic pathway.

Stability and Function of Mammalian Lethal Giant Larvae-1 Oncoprotein Are Regulated by the Scaffolding Protein RanBPM

“…RanBPM promotes BACE1 processing of amyloid precursor protein and amyloid ␤ peptide generation (26). Recently, RanBPM was reported as an activator of proapoptotic pathway in response to DNA damage (29).In this study, we showed exogenous and endogenous interaction between Mgl-1 and RanBPM by co-immunoprecipitation studies. We also demonstrated that the N-terminal region of Mgl-1 was responsible for binding with RanBPM, and the Mgl-1-interacting region in RanBPM was mapped to the N-terminal region containing SPRY domain.…”

“…RanBPM promotes BACE1 processing of amyloid precursor protein and amyloid ␤ peptide generation (26). Recently, RanBPM was reported as an activator of proapoptotic pathway in response to DNA damage (29).…”

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

“…Although RanBP9 has previously been implicated in the promotion of cell death, the mechanisms of such activity are unknown. 25 We have previously shown that RanBP9 accelerates APP, LRP, and b1-integrin endocytosis, simultaneously leading to increased Ab generation in vitro and in vivo 6,7 and disruption of focal adhesions. 9 As such, our observation that RanBP9 activates/dephosphorylates cofilin is consistent with the known role of the integrin-LIMK pathway in the inactivation/phosphorylation of cofilin, although the Slingshot pathway cannot be ruled out.…”

Insulin signalling in mushroom body neurons regulates feeding behaviour inDrosophilalarvae

“…RanBPM has been implicated in various signalling pathways as a putative scaffolding protein (e.g. Bai et al, 2003;Mikolajczyk et al, 2003;Menon et al, 2004;Brunkhorst et al, 2005;Hafizi et al, 2005;Haase et al, 2008;Atabakhsh et al, 2009;Gong et al, 2009;Kim et al, 2009;Chang et al, 2010) (reviewed by Murrin and Talbot, 2007). RanBPM expression in PC12 cells promotes TrkB-dependent activation of the serine-threonine kinase Akt, a target of insulin signalling (Yin et al, 2010).…”