Induction of tumor inhibition and apoptosis by a candidate tumor suppressor gene DRR1 on 3p21.1

Liu, Quan; Zhao, Xinyu; Bai, Ruizhen; Liang, Shufang; Nie, Chao; Zhu, Yuan Xiao; Wang, Chunting; Wu, Yang Chang; Chen, Lijuan; Wei, Yuquan

doi:10.3892/or_00000538

Cited by 11 publications

(2 citation statements)

References 29 publications

(42 reference statements)

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“…Later was demonstrated by introducing the protein to cancer cell lines lacking DRR1 and suppressing cell growth (Zhao et al, 2007). Following studies showed loss of DRR1 mRNA in 6 of 7 human cancer cell lines and lack of DRR1 protein when immunostaining specimens of human non-small cell lung cancer (Liu et al, 2009). Murine in vitro and in vivo studies revealed reduction of cell growth and apoptosis when introducing DRR1 into DRR1-negative-expressing A549 cell lines and injecting Drr1 cDNA (complementary deoxyribonucleic acid) into mice with A549 xenograft tumors (Liu et al, 2009).…”

Section: Drr1 (Down Regulated In Renal Cell Carcinoma) Proteinmentioning

confidence: 99%

“…Following studies showed loss of DRR1 mRNA in 6 of 7 human cancer cell lines and lack of DRR1 protein when immunostaining specimens of human non-small cell lung cancer (Liu et al, 2009). Murine in vitro and in vivo studies revealed reduction of cell growth and apoptosis when introducing DRR1 into DRR1-negative-expressing A549 cell lines and injecting Drr1 cDNA (complementary deoxyribonucleic acid) into mice with A549 xenograft tumors (Liu et al, 2009). Through development of DRR1-specific polyclonal antibodies, examination of the expression pattern was possible for the first time in a large scale (Asano et al, 2010).…”

Section: Drr1 (Down Regulated In Renal Cell Carcinoma) Proteinmentioning

confidence: 99%

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The role of the actin-interacting protein DRR1 in shaping neuronal stress resilience

Tschesnokowa

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Subject of this thesis was the investigation of the actin-interacting and glucocorticoid-sensitive Protein DRR1 (or Fam107a) and its role in promoting stress resilience in the murine hippocampus. We proposed the hypothesis that DRR1 through its actin-binding properties specifically modulates neuronal actin dynamics and promotes resilience through synaptic plasticity leading to subsequently improvement of cognitive performance and social behavior. The accompanied AMPA-receptor transport could create an efficient way regulating neural function and complex behavior during stress episodes. By utilizing fluorescent immunohistochemistry, we showed basal expression of DRR1 primarily in the murine cerebellum and hippocampal CA3 and CA1 area. Co-staining with different cell marker proteins showed DRR1 expression in neurons, microglia and especially in astrocytic end-feet, which create contact to the brain vasculature. To test whether DRR1 and AMPA receptor function correlate to modulate stress-associated consequences, primary hippocampal neuron cultures were transduced with adeno-associated virus (AAV) for overexpression or suppression of the protein. Western Blot analysis showed a positive correlation between the AMPA-receptor subunit GluR2 and DRR1 amounts. Further the application of the proximity ligation assay (PLA) in untreated neural cultures indicated interaction between DRR1 and the AMPA receptor subunit GluR2. To address whether DRR1 even affects AMPAR trafficking we performed the “newly inserted assay” after AAV-treatment of primary hippocampal neuron cultures. Suppression of DRR1 revealed less newly inserted GluR2 subunits as compared to controls. Inconclusive were the results upon DRR1 overexpression, however they point to no changes. In the second part we correlated behavioral phenotypes originating from in vivo overexpression and suppression of DRR1 in the murine hippocampus with potential alterations in neuronal morphology. Therefore, in vitro analysis was performed utilizing AAV transduced primary hippocampal cultures overexpressing or suppressing DRR1. Synchronously the viral vector included a green fluorescent protein (GFP) being expressed throughout the complete neural cell. GFP staining was used to verify successful transfection and for reconstruction of dendritic arbors and dendritic stretches for spine classification. DRR1 suppression showed reduced total spine numbers especially evoked by reduced numbers of immature spine classes – namely long thin spines and filopodia. Whereas mature mushroom spines and stubby spines were unaffected. By overexpressing DRR1, tendencies inclined against higher total dendritic lengths, branch points and increased dendritic arbors in comparison to controls. In regard of spines, total numbers were unaffected. However, mature mushroom spines were significantly declined in numbers, but compensated by increased numbers of immature long thin spines and filopodia. Chronic social defeat stress (CSDS) is widely used in mouse models to study the effects of stress and resilience. We exposed C57Bl/6J mice expressing GFP under the Thy1 promoter CSDS and categorized them into resilient (R+/-), susceptible (R-/-) and non-learning (R+/+) mice following a modified social interaction test (MSIT). We found alterations in CA1 spine compositions with resilient animals resembling the untreated phenotype. Stress susceptible and non-learning animals displayed reduced numbers in stubby spines with simultaneous increases in mature mushroom spines. In addition, we could detect a tendency towards more immature spines in susceptible animals and non-learners, mirroring our in vitro results. Finally, we present a different investigative approach in this thesis. Sequenced acute stress was previously found to compromise cognition including spine loss. We aimed to investigate the implication of acute stress on DRR1 levels and its occurrence in diverse cell types of the brain. We subjected one group of C57Bl/6J mice to acute stress and injected another group with the artificial glucocorticoid DEX. Six hours post stress, animals were perfused and brains were subsequently immunobiologically analyzed. We found DRR1 protein levels elevated in the hippocampus of stressed and DEX-treated animals compared to controls. Interestingly, DRR1 seemed was especially elevated in endothelial cells. This coincides with our investigations finding DRR1 present in astrocytic end-feet under basal conditions and might claim a participation of DRR1 in the blood-brain-barrier integrity. Our results show DRR1 as actin-interacting and glucocorticoid-sensitive gene affecting structural plasticity of hippocampal spines. Moreover, DRR1 directly interacts with AMPA glutamate receptors and presumably is involved in AMPA trafficking to the postsynaptic membrane. In addition, this study could demonstrate that DRR1 is expressed by other cell types of the brain. Of special interest is DRR1’s occurrence in astrocytic end-feet and endothelial cells suggesting a role as integrator of cell-cell communication and to this end also acting as modifier of stress-induced consequences at the neurovascular unit. In vivo data of chronically stressed mice displayed no phenotypic differences in hippocampal pyramidal neurons of resilient animals as compared to unstressed mice. Morphological alterations of spine structures were particularly visible in stress susceptible and non-learning animals. Integrating our findings with existing behavioral data, we can conclude that DRR1 plays a role in stress resilience whereby it needs to be expressed in a tightly managed homeostatic equilibrium.

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Section: Drr1 (Down Regulated In Renal Cell Carcinoma) Proteinmentioning

confidence: 99%

Section: Drr1 (Down Regulated In Renal Cell Carcinoma) Proteinmentioning

confidence: 99%

The role of the actin-interacting protein DRR1 in shaping neuronal stress resilience

Tschesnokowa

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Enhanced gemcitabine-mediated cell killing of human lung adenocarcinoma by vector-based RNA interference against PLK1

Zhao

Nie

Liang

et al. 2012

Biomedicine & Pharmacotherapy

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A novel nuclear complex of DRR1, F-actin and COMMD1 involved in NF-κB degradation and cell growth suppression in neuroblastoma

Akashi

et al. 2017

Oncogene

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Downregulated in renal cell carcinoma 1 (DRR1) has important roles in tumor cell growth, neuron survival and spine formation, and was recently shown to bind actin. However, the roles of nuclear DRR1 remain largely unexplored. Here, we identified an interaction between filamentous actin (F-actin) and DRR1 in the nucleus, and demonstrated that copper metabolism MURR1 domain-containing 1 (COMMD1) is another binding partner of DRR1. Accordingly, DRR1, F-actin and COMMD1 were shown to form a complex in the nucleus, and the stability of COMMD1 was enhanced in this complex. Increased nuclear COMMD1 in turn promoted the degradation of NF-κB. In addition, DRR1 and COMMD1 suppressed the cyclin D1 expression, G1/S transition and cell proliferation of neuroblastoma cells. The binding between DRR1 and F-actin in the nucleus was required for these events. Consistent with these facts, low expressions of DRR1 were associated with tumorigenesis of human neuroblastoma and its mouse model. This study has thus revealed a novel nuclear complex of F-actin, DRR1 and COMMD1 that is involved in NF-κB degradation and cell cycle suppression in neuroblastoma cells.

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Induction of tumor inhibition and apoptosis by a candidate tumor suppressor gene DRR1 on 3p21.1

Cited by 11 publications

References 29 publications

The role of the actin-interacting protein DRR1 in shaping neuronal stress resilience

The role of the actin-interacting protein DRR1 in shaping neuronal stress resilience

Enhanced gemcitabine-mediated cell killing of human lung adenocarcinoma by vector-based RNA interference against PLK1

A novel nuclear complex of DRR1, F-actin and COMMD1 involved in NF-κB degradation and cell growth suppression in neuroblastoma

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