Off-Target Effects of the Septin Drug Forchlorfenuron on Nonplant Eukaryotes

Heasley, Lydia R.; García, Galo; McMurray, Michael A.

doi:10.1128/ec.00191-14

Cited by 31 publications

(29 citation statements)

References 68 publications

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“…A recent study demonstrated that FCF alters mitochondrial morphology (61). Based on this observation, the authors suggested the existence of non-septin targets of FCF, but no such targets have been identified (61). Moreover, no evidence has been presented that the morphological changes in mitochondria are independent of the FCF-induced impairment of assembly and disassembly of septins that are known to reside in mitochondria (62).…”

Section: Septin-containing Protein Complexes Undergo Continuous Reorgmentioning

confidence: 94%

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Septin Dynamics Are Essential for Exocytosis

Tokhtaeva

Capri²,

Marcus

et al. 2015

Journal of Biological Chemistry

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Background: Septins serve as scaffolds for membrane-associated protein complexes. Results: Knockdown of septin-2 or disruption of septin assembly/disassembly impairs interactions between exocytic proteins and inhibits late steps of exocytosis. Conclusion: Septins undergo dynamic reorganization to facilitate localized and timely interactions between exocytosis-essential proteins. Significance: Both the presence of septin-2 and active reorganization of septin oligomers are required for exocytosis.

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Section: Septin-containing Protein Complexes Undergo Continuous Reorgmentioning

confidence: 94%

“…4, 7C, and 8D). A recent study demonstrated that FCF alters mitochondrial morphology (61). Based on this observation, the authors suggested the existence of non-septin targets of FCF, but no such targets have been identified (61).…”

Section: Septin-containing Protein Complexes Undergo Continuous Reorgmentioning

confidence: 99%

Septin Dynamics Are Essential for Exocytosis

Tokhtaeva

Capri²,

Marcus

et al. 2015

Journal of Biological Chemistry

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“…3B). To date the only known septin inhibitor is FCF , but its specificity is questionable and off-target effects have recently been described (Heasley et al, 2014). It will therefore be necessary to develop systems to screen for novel cellpermeable septin inhibitors that alter septin filament structure and inhibit cytokinesis of only the targeted cell types.…”

Section: Septin Inhibitors As Directed Therapy Against Solid Tumorsmentioning

confidence: 99%

Sep(t)arate or not – how some cells take septin-independent routes through cytokinesis

Menon

Gaestel

2015

Journal of Cell Science

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Cytokinesis is the final step of cell division, and is a process that requires a precisely coordinated molecular machinery to fully separate the cytoplasm of the parent cell and to establish the intact outer cell barrier of the daughter cells. Among various cytoskeletal proteins involved, septins are known to be essential mediators of cytokinesis. In this Commentary, we present recent observations that specific cell divisions can proceed in the absence of the core mammalian septin SEPT7 and its Drosophila homolog Peanut (Pnut) and that thus challenge the view that septins have an essential role in cytokinesis. In the pnut mutant neuroepithelium, orthogonal cell divisions are successfully completed. Similarly, in the mouse, Sept7-null mutant early embryonic cells and, more importantly, planktonically growing adult hematopoietic cells undergo productive proliferation. Hence, as discussed here, mechanisms must exist that compensate for the lack of SEPT7 and the other core septins in a celltype-specific manner. Despite there being crucial non-canonical immune-relevant functions of septins, septin depletion is well tolerated by the hematopoietic system. Thus differential targeting of cytokinesis could form the basis for more specific anti-proliferative therapies to combat malignancies arising from cell types that require septins for cytokinesis, such as carcinomas and sarcomas, without impairing hematopoiesis that is less dependent on septin.

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“…Both siRNA knockdown of septin-2/septin-9 and inhibition of septin filament assembly-disassembly with FCF induce ErbB2 degradation (Fig. 4A), confirming that degradation of ErbB2 is a result of interference with septin dynamics rather than an unknown, alternate target of FCF [72]. By re-organizing septin oligomers, FCF disrupts ErbB2-septin complexes at the plasma membrane and induces internalization and degradation of ErbB2.…”

Section: Discussionmentioning

confidence: 62%

Septin oligomerization regulates persistent expression of ErbB2/HER2 in gastric cancer cells

Marcus

Tokhtaeva

Turdikulova

et al. 2016

Biochemical Journal

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Septins are a family of cytoskeletal GTP-binding proteins that assemble into membrane-associated hetero-oligomers and organize scaffolds for recruitment of cytosolic proteins or stabilization of membrane proteins. Septins have been implicated in a diverse range of cancers, including gastric cancer, but the underlying mechanisms remain unclear. The hypothesis tested here is that septins contribute to cancer by stabilizing the receptor tyrosine kinase ErbB2, an important target for cancer treatment. Septins and ErbB2 were highly over-expressed in gastric cancer cells. Immunoprecipitation followed by mass-spectrometry analysis identified ErbB2 as a septin-interacting protein. Knockdown of septin-2 or cell exposure to forchlorfenuron (FCF), a well-established inhibitor of septin oligomerization, decreased surface and total levels of ErbB2. These treatments had no effect on EGFR, emphasizing the specificity and functionality of the septin-ErbB2 interaction. The level of ubiquitylated ErbB2 at the plasma membrane was elevated in cells treated with FCF, which was accompanied by a decrease in co-localization of ErbB2 with septins at the membrane. Cathepsin B inhibitor, but not bafilomycin or lactacystin, prevented FCF-induced decrease in total ErbB2 by increasing accumulation of ubiquitylated ErbB2 in lysosomes. Therefore, septins protect ErbB2 from ubiquitylation, endocytosis, and lysosomal degradation. The FCF-induced degradation pathway is distinct from and additive with the degradation induced by inhibiting ErbB2 chaperone HSP90. These results identify septins as novel regulators of ErbB2 expression that contribute to the remarkable stabilization of the receptor at the plasma membrane of cancer cells and may provide a basis for the development of new ErbB2-targeting anti-cancer therapies.

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Off-Target Effects of the Septin Drug Forchlorfenuron on Nonplant Eukaryotes

Cited by 31 publications

References 68 publications

Septin Dynamics Are Essential for Exocytosis

Septin Dynamics Are Essential for Exocytosis

Sep(t)arate or not – how some cells take septin-independent routes through cytokinesis

Septin oligomerization regulates persistent expression of ErbB2/HER2 in gastric cancer cells

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