Septin 9 isoform 1 (SEPT9_i1) specifically interacts with importin‐α7 to drive hypoxia‐inducible factor (HIF)‐1α nuclear translocation

Tazat, Keren; Schindler, Susanne; Depping, Reinhard; Mabjeesh, Nicola J.

doi:10.1002/cm.21450

Cited by 8 publications

(4 citation statements)

References 31 publications

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“…The notion that blebgenerated curvature could recruit septins to the plasma membrane upon cell detachment is supported by previous work 39,40 , though we found no reports of an explicit connection between bleb-related surface curvature and septin recruitment. Septins are known to scaffold and regulate factors from diverse signaling pathways [41][42][43][44] , including pro-survival pathways in cancer cells such as HIF-1 [45][46][47] , EGFR 48 , MET 49,50 , JNK 51 , and HER2 52 . Therefore, we hypothesized that bleb-dependent anoikis resistance could be achieved through recruitment of curvature-sensitive septin proteins to the plasma membrane via bleb-generated curvature, where they promote pro-survival signaling.…”

Section: Bleb-generated Plasma Membrane Curvature Drives the Formation Of Cortical Septin Structuresmentioning

confidence: 99%

Blebs Promote Cell Survival by Assembling Oncogenic Signaling Hubs

Driscoll

et al. 2021

Preprint

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For most human cells, anchorage is a key necessity for survival. Cell-substrate adhesion activates diverse signaling pathways, without which cells undergo anoikis – a form of programmed cell death1. Acquisition of anoikis resistance is a pivotal step in cancer disease progression, as metastasizing cancer cells often lose firm attachment to surrounding tissue2–5. In these poorly attached states, cells often adopt rounded morphologies and form small hemispherical plasma membrane protrusions called blebs6–13. Bleb function has long been investigated in the context of amoeboid migration but is far less deeply examined in other scenarios14–19. Here we show by quantitative subcellular 3D imaging and manipulation of cell morphological states that blebbing triggers the formation of membrane-proximal signaling hubs that initiate signaling cascades leading to anoikis resistance. Specifically, in melanoma cells we discovered that blebbing generates plasma membrane contours that recruit curvature sensing septin proteins, which scaffold constitutively active mutant NRAS and effectors, driving the upregulation of ERK and PI3K signaling. Inhibition of blebs or septins has little effect on the survival of well-adhered cells, but in detached cells causes NRAS mislocalization, reduced MAPK and PI3K signaling, and ultimately, death. These data unveil an unanticipated morphological requirement for mutant NRAS to operate as an effective oncoprotein, suggesting novel clinical targets for the treatment of NRAS-driven melanoma. Furthermore, they define an unforeseen role for blebs as potent signaling organelles capable of integrating myriad cellular information flows into concerted signaling responses, in this case granting robust anoikis resistance.Abstract Figure

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Section: Bleb-generated Plasma Membrane Curvature Drives the Formation Of Cortical Septin Structuresmentioning

confidence: 99%

Blebs Promote Cell Survival by Assembling Oncogenic Signaling Hubs

Driscoll

et al. 2021

Preprint

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“…However, it is not yet known which isotypes of importin α drive the nuclear translocation of HIF1 α in stem cells. In addition, a recent study of prostate cancer cells showed that isoform 1 of Septin 9, a GTP-binding protein, facilitates HIF1 α nuclear translocation via its interaction with importin α 7 (112). Likewise, calcium stimulates interactions between S100A6 and armadillo repeats of importin α , followed by the inhibition of NLS formation of cargo–importin α transport complexes that regulate the nuclear translocation of cargo proteins (113).…”

Section: Hif1α Regulatory Factorsmentioning

confidence: 99%

Role of HIF1α Regulatory Factors in Stem Cells

Lee¹,

Jung²,

Choi³

et al. 2019

IJSC

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Hypoxia-inducible factor 1 (HIF1) is a master transcription factor that induces the transcription of genes involved in the metabolism and behavior of stem cells. HIF1-mediated adaptation to hypoxia is required to maintain the pluripotency and survival of stem cells under hypoxic conditions. HIF1 activity is well known to be tightly controlled by the alpha subunit of HIF1 (HIF1 α ). Understanding the regulatory mechanisms that control HIF1 activity in stem cells will provide novel insights into stem cell biology under hypoxia. Recent research has unraveled the mechanistic details of HIF1 α regulating processes, suggesting new strategies for regulating stem cells. This review summarizes recent experimental studies on the role of several regulatory factors (including calcium, 2-oxoglutarate-dependent dioxygenase, microtubule network, importin, and coactivators) in regulating HIF1 α activity in stem cells.

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“…Therefore, research on the target of Hif-1 α has currently become a topic of great interest. It has been shown that Sept9 can bind and stabilize Hif-1 α , promote its transcriptional expression, and promote angiogenesis and tumor growth [ 12 , 13 ]. By using Chinese Glioma Genome Atlas (CGGA) gene correlation analysis, it was discovered the significant positive correlation between Sept9 and Hif-1 α .…”

Section: Introductionmentioning

confidence: 99%

Cinnamaldehyde Downregulation of Sept9 Inhibits Glioma Progression through Suppressing Hif-1α via the Pi3k/Akt Signaling Pathway

Wang

Fu³

et al. 2022

Disease Markers

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Purpose. Cinnamaldehyde (CA) is the main ingredient in cinnamon, and it has been proven to have an inhibitory effect on many different tumor types. However, it lacks effect on glioma. This paper explores the effect CA has on glioma cells U87 and U251 at the cellular and molecular levels. Methods. The relationship between Hif-1α and Sept9 was found by CGGA. Cell Viability Assay (CCK8) was made to detect the proliferation ability. The scratch experiment and the transwell experiment were applied to the migration and invasion ability. Annexin V-FITC/PI were used to detect the cell apoptosis. Western blotting was used to determine the specified protein level. Results. Cell proliferation assay results revealed CA to inhibit the proliferation of glioma cells in a dose-dependent manner. It promoted apoptosis for upregulating the expression of Bax and downregulating the expression of Bcl-2. Wound Healing Assay and transwell test found CA to have anti-invasion ability and that it upregulated the expression of E-cadherin and downregulated the expressions of MMP-2 and MMP-9. The molecular mechanism was studied from a tumor microenvironment (TME) perspective. Pi3k inhibitor (LY294002) was used for interfering with cells, and the results found CA to demonstrate a similar effect. Hif-1α and Sept9 expressions were inhibited, and Akt and p-Akt were also inhibited. By using CoCl2 to make hypoxia, CA was discovered to inhibit the high expression of Hif-1α and Sept9, demonstrating a correlation with the Pi3k/Akt pathway. It is suggested that the mechanism of Sept9 under hypoxia regulation can be realized through the Pi3k/Akt pathway. Conclusions. This study proves for the first time that CA is an effective drug for inhibiting the proliferation of glioma through Sept9 and reveals Sept9 to be related to the Pi3k/Akt pathway in terms of tumor microenvironment, providing a molecular basis for the further study of CA in glioma treatment.

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Septin 9 isoform 1 (SEPT9_i1) specifically interacts with importin‐α7 to drive hypoxia‐inducible factor (HIF)‐1α nuclear translocation

Cited by 8 publications

References 31 publications

Blebs Promote Cell Survival by Assembling Oncogenic Signaling Hubs

Blebs Promote Cell Survival by Assembling Oncogenic Signaling Hubs

Role of HIF1α Regulatory Factors in Stem Cells

Cinnamaldehyde Downregulation of Sept9 Inhibits Glioma Progression through Suppressing Hif-1α via the Pi3k/Akt Signaling Pathway

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