Non-Overlapping Distributions and Functions of the VDAC Family in Ciliogenesis

Majumder, Shubhra; Cash, Ayla; Fisk, Harold A.

doi:10.3390/cells4030331

Cited by 15 publications

(20 citation statements)

References 65 publications

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“… 52 The Fisk lab recently discovered that VDAC1 can localize to centrosomes. 63 Our result confirmed their find ( Supplementary Figure 6f ). In this paper, we identified Mps1 as a novel regulator of VDAC1; Mps1 binding to VDAC1 can attribute to tumor cell survival by regulating cytochrome c release.…”

Section: Discussionsupporting

confidence: 91%

Mps1 kinase regulates tumor cell viability via its novel role in mitochondria

Zhang

Ling²,

Guo

et al. 2016

Cell Death Dis

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Targeting mitotic kinase monopolar spindle 1 (Mps1) for tumor therapy has been investigated for many years. Although it was suggested that Mps1 regulates cell viability through its role in spindle assembly checkpoint (SAC), the underlying mechanism remains less defined. In an endeavor to reveal the role of high levels of mitotic kinase Mps1 in the development of colon cancer, we unexpectedly found the amount of Mps1 required for cell survival far exceeds that of maintaining SAC in aneuploid cell lines. This suggests that other functions of Mps1 besides SAC are also employed to maintain cell viability. Mps1 regulates cell viability independent of its role in cytokinesis as the genetic depletion of Mps1 spanning from metaphase to cytokinesis affects neither cytokinesis nor cell viability. Furthermore, we developed a single-cycle inhibition strategy that allows disruption of Mps1 function only in mitosis. Using this strategy, we found the functions of Mps1 in mitosis are vital for cell viability as short-term treatment of mitotic colon cancer cell lines with Mps1 inhibitors is sufficient to cause cell death. Interestingly, Mps1 inhibitors synergize with microtubule depolymerizing drug in promoting polyploidization but not in tumor cell growth inhibition. Finally, we found that Mps1 can be recruited to mitochondria by binding to voltage-dependent anion channel 1 (VDAC1) via its C-terminal fragment. This interaction is essential for cell viability as Mps1 mutant defective for interaction fails to main cell viability, causing the release of cytochrome c. Meanwhile, deprivation of VDAC1 can make tumor cells refractory to loss of Mps1-induced cell death. Collectively, we conclude that inhibition of the novel mitochondrial function Mps1 is sufficient to kill tumor cells.

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Section: Discussionsupporting

confidence: 91%

Mps1 kinase regulates tumor cell viability via its novel role in mitochondria

Zhang

Ling²,

Guo

et al. 2016

Cell Death Dis

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“…Positive regulation of cilia/flagella assembly in centrosomes/basal bodies and centriolar satellites has been ascribed to VDAC2 [125]. In pulmonary artery endothelial cells (PAEC), both VDAC1 and 2 were shown to interact with eNOS (nitric oxide synthase), VDAC2 had a higher expression level than other isoforms, and upon VDAC2 silencing eNOS could not be stimulated by calcium [69].…”

Section: Vdac2's Other Functionsmentioning

confidence: 99%

VDAC2-specific cellular functions and the underlying structure

Naghdi

Hajnóczky

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Voltage Dependent Anion-selective Channel 2 (VDAC2) contributes to oxidative metabolism by sharing a role in solute transport across the outer mitochondrial membrane (OMM) with other isoforms of the VDAC family, VDAC1 and VDAC3. Recent studies revealed that VDAC2 also has a distinctive role in mediating sarcoplasmic reticulum to mitochondria local Ca2+ transport at least in cardiomyocytes, which is unlikely to be explained simply by the expression level of VDAC2. Furthermore, a strictly isoform-dependent VDAC2 function was revealed in the mitochondrial import and OMM-permeabilizing function of pro-apoptotic Bcl-2 family proteins, primarily Bak in many cell types. In addition, emerging evidence indicates a variety of other isoform-specific engagements for VDAC2. Since VDAC isoforms display 75% sequence similarity, the distinctive structure underlying VDAC2-specific functions is an intriguing problem. In this paper we summarize studies of VDAC2 structure and functions, which suggest a fundamental and exclusive role for VDAC2 in health and disease. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

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“…VDAC oligomerization, followed by VDAC overexpression, may represent a common mechanism by which various apoptogens act through different initiating cascades 6 . Moreover, VDAC function extends beyond the mitochondria, and VDACs localize to the basal body of the primary cilium, where VDAC1 and VDAC3 negatively regulate ciliogenesis 7 . Recent reports show that dysfunction of primary cilia increases apoptotic cell death in glioblastoma, or induce neuron apoptosis in mice 8 , 9 .…”

Section: Introductionmentioning

confidence: 99%

Loss of primary cilia promotes mitochondria-dependent apoptosis in thyroid cancer

Lee

Park

Sul

et al. 2021

Sci Rep

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The primary cilium is well-preserved in human differentiated thyroid cancers such as papillary and follicular carcinoma. Specific thyroid cancers such as Hürthle cell carcinoma, oncocytic variant of papillary thyroid carcinoma (PTC), and PTC with Hashimoto’s thyroiditis show reduced biogenesis of primary cilia; these cancers are often associated the abnormalities in mitochondrial function. Here, we examined the association between primary cilia and the mitochondria-dependent apoptosis pathway. Tg-Cre;Ift88flox/flox mice (in which thyroid follicles lacked primary cilia) showed irregularly dilated follicles and increased apoptosis of thyrocytes. Defective ciliogenesis caused by deleting the IFT88 and KIF3A genes from thyroid cancer cell lines increased VDAC1 oligomerization following VDAC1 overexpression, thereby facilitating upregulation of mitochondria-dependent apoptosis. Furthermore, VDAC1 localized with the basal bodies of primary cilia in thyroid cancer cells. These results demonstrate that loss-of-function of primary cilia results in apoptogenic stimuli, which are responsible for mitochondrial-dependent apoptotic cell death in differentiated thyroid cancers. Therefore, regulating primary ciliogenesis might be a therapeutic approach to targeting differentiated thyroid cancers.

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Non-Overlapping Distributions and Functions of the VDAC Family in Ciliogenesis

Cited by 15 publications

References 65 publications

Mps1 kinase regulates tumor cell viability via its novel role in mitochondria

Mps1 kinase regulates tumor cell viability via its novel role in mitochondria

VDAC2-specific cellular functions and the underlying structure

Loss of primary cilia promotes mitochondria-dependent apoptosis in thyroid cancer

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