Neuronal Apoptosis Induced by Selective Inhibition of Rac GTPase versus Global Suppression of Rho Family GTPases Is Mediated by Alterations in Distinct Mitogen-activated Protein Kinase Signaling Cascades

Stankiewicz, Trisha R.; Ramaswami, Sai Anandi; Bouchard, Ron J.; Aktories, Klaus; Linseman, Daniel A.

doi:10.1074/jbc.m114.575217

Cited by 26 publications

(23 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Impaired differentiation and apoptosis have been reported in Rac1-KO telencephalon-derived neurons (Chen et al, 2009). In addition, selective inhibition of Rac has been reported to induce apoptosis in CGNs (Stankiewicz et al, 2015). Rac1/Rac3-DKO CGNs exhibited: (1) a normal pattern of differentiation until the expression of NeuN, a marker for postmitotic CGNs, was seen in the deepest layer of the EGL at P5; (2) few Map2-positive neurites in cerebellar microexplants and disrupted development of vertical dendrites at P8; and (3) robust apoptosis at the deep layer of the EGL, a premigratory zone for preparing the subsequent radial migration (Yamasaki et al, 2001), at P8.…”

Section: Discussionmentioning

confidence: 99%

Novel role of Rac-Mid1 signaling in medial cerebellar development

et al. 2017

View full text Add to dashboard Cite

Rac signaling impacts a relatively large number of downstream targets; however, few studies have established an association between Rac pathways and pathological conditions. In the present study, we generated mice with double knockout of Rac1 and Rac3 (Atoh1-Cre;Rac1 flox/flox ;Rac3 −/− ) in cerebellar granule neurons (CGNs). We observed impaired tangential migration at E16.5, as well as numerous apoptotic CGNs at the deepest layer of the external granule layer (EGL) in the medial cerebellum of Atoh1-Cre; Rac1 flox/flox ;Rac3 −/− mice at P8. Atoh1-Cre;Rac1 flox/flox ;Rac3CGNs differentiated normally until expression of p27 kip1 and NeuN in the deep EGL at P5. Primary CGNs and cerebellar microexplants from Atoh1-Cre;Rac1 flox/flox ;Rac3 −/− mice exhibited impaired neuritogenesis, which was more apparent in Map2-positive dendrites. Such findings suggest that impaired tangential migration and final differentiation of CGNs have resulted in decreased cerebellum size and agenesis of the medial internal granule layer, respectively. Furthermore, Rac depleted/deleted cells exhibited decreased levels of Mid1 and impaired mTORC1 signaling. Mid1 depletion in CGNs produced mild impairments in neuritogenesis and reductions in mTORC1 signaling. Thus, a novel Rac-signaling pathway (Rac1-Mid1-mTORC1) may be involved in medial cerebellar development.

show abstract

Section: Discussionmentioning

confidence: 99%

Novel role of Rac-Mid1 signaling in medial cerebellar development

et al. 2017

View full text Add to dashboard Cite

show abstract

“…This pathway plays an important role in regulating neuronal survival and inhibiting neuronal apoptosis [43, 44]. Rac1 has been shown to promote cell survival via Akt [45].…”

Section: Discussionmentioning

confidence: 99%

Treg Cells Protect Dopaminergic Neurons against MPP+ Neurotoxicity via CD47-SIRPA Interaction

Huang

Cao

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Regulatory T (Treg) cells have been associated with neuroprotection by inhibiting microglial activation in animal models of Parkinson's disease (PD), a progressive neurodegenerative disease characterized by dopaminergic neuronal loss in the nigrostriatal system. Herein, we show that Treg cells directly protect dopaminergic neurons against 1-methyl-4-phenylpyridinium (MPP⁺) neurotoxicity via an interaction between the two transmembrane proteins CD47 and signal regulatory protein α (SIRPA). Methods: Primary ventral mesencephalic (VM) cells or VM neurons were pretreated with Treg cells before MPP⁺ treatment. Transwell co-culture of Treg cells and VM neurons was used to assess the effects of the Treg cytokines transforming growth factor (TGF)-β1 and interleukin (IL)-10 on dopaminergic neurons. Live cell imaging system detected a dynamic contact of Treg cells with VM neurons that were stained with CD47 and SIRPA, respectively. Dopaminergic neuronal loss, which was assessed by the number of tyrosine hydroxylase (TH)-immunoreactive cells, was examined after silencing CD47 in Treg cells or silencing SIRPA in VM neurons. Results: Treg cells prevented MPP⁺-induced dopaminergic neuronal loss and glial inflammatory responses. TGF-β1 and IL-10 secreted from Treg cells did not significantly prevent MPP⁺-induced dopaminergic neuronal loss in transwell co-culture of Treg cells and VM neurons. CD47 and SIRPA were expressed by Treg cells and VM neurons, respectively. CD47-labeled Treg cells dynamically contacted with SIRPA-labeled VM neurons. Silencing CD47 gene in Treg cells impaired the ability of Treg cells to protect dopaminergic neurons against MPP⁺ toxicity. Similarly, SIRPA knockdown in VM neurons reduced the ability of Treg cell neuroprotection. Rac1/Akt signaling pathway in VM neurons was activated by CD47-SIRPA interaction between Treg cells and the neurons. Inhibiting Rac1/Akt signaling in VM neurons compromised Treg cell neuroprotection. Conclusion: Treg cells protect dopaminergic neurons against MPP⁺ neurotoxicity by a cell-to-cell contact mechanism underlying CD47-SIRPA interaction and Rac1/Akt activation.

show abstract

“…Studies have suggested that Rac acts as an upstream activator of JNK/c-Jun signaling [9,16,17], while others have suggested that Rac can also suppress the JNK pathway [10,18]. To expand our current studies related to the inhibition of Rac activity and its relation to apoptosis in OSC-19 and HOC313 cells, we investigated downstream signaling of the Rac pathway.…”

Section: Resultsmentioning

confidence: 99%

“…One mechanism that requires additional elucidation is the regulation of JNK activity after suppression of Rac. Many studies have indicated that Rac acts as an upstream activator of JNK signaling in certain cells [9,16,17], while others have reported that Rac can suppress the JNK pathway [10,18]. In general, whether Rac positively or negatively regulates the JNK pathway may primarily depends on the specific cancer cell type.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of decreased Rac activity and malignant state on oral squamous cell carcinoma

Al-Shareef

Matsuoka

Kogo

et al. 2019

Preprint

View full text Add to dashboard Cite

23Rac proteins, members of the Rho family of small GTP-binding proteins, have been 24 implicated in transducing a number of signals for various biological mechanisms, 25 including cell cytoskeleton organization, transcription, proliferation, migration, and 26 cancer cell motility. Among human cancers, Rac proteins are highly activated by either 27 overexpression of the genes, up-regulation of the protein, or by mutations that allow the 28 protein to elude normal regulatory signaling pathways. Rac proteins are involved in 29 controlling cell survival and apoptosis. The effects of Rac inhibition by the Rac-specific 30 small molecule inhibitor NSC23766 or by transfection of dominant negative Rac (Rac-31 DN) were examined on three human-derived oral squamous cell carcinoma cell lines 32 that exhibit different malignancy grades, OSC-20 (grade 3), OSC-19 (grade 4C), and 33 HOC313 (grade 4D). Upon suppression of Rac, OSC-19 and HOC313 cells showed 34 significant decreases in Rac activity and resulted in condensation of the nuclei and up-35 regulation of c-Jun N-terminal kinase (JNK), leading to caspase-dependent apoptosis. In 36 contrast, OSC-20 cells showed only a slight decrease in Rac activity, which resulted in 37 slight activation of JNK and no change in the nuclei. Fibroblasts treated with 38 NSC23766 also showed only a slight decrease in Rac activity with no change in the 39 nuclei or JNK activity. Our results indicated that apoptosis elicited by the inhibition of 40 Rac depended on the extent of decreased Rac activity and the malignant state of the 41 squamous cell carcinoma. In addition, activation of JNK strongly correlated with 42 apoptosis. Rac inhibition may represent a novel therapeutic approach for cancer 43 treatment.44

show abstract

Neuronal Apoptosis Induced by Selective Inhibition of Rac GTPase versus Global Suppression of Rho Family GTPases Is Mediated by Alterations in Distinct Mitogen-activated Protein Kinase Signaling Cascades

Cited by 26 publications

References 45 publications

Novel role of Rac-Mid1 signaling in medial cerebellar development

Novel role of Rac-Mid1 signaling in medial cerebellar development

Treg Cells Protect Dopaminergic Neurons against MPP+ Neurotoxicity via CD47-SIRPA Interaction

Effects of decreased Rac activity and malignant state on oral squamous cell carcinoma

Contact Info

Product

Resources

About