Microtubules and Their Role in Cellular Stress in Cancer

Parker, Amelia L.; Kavallaris, Maria; McCarroll, Joshua A.

doi:10.3389/fonc.2014.00153

Cited by 328 publications

(287 citation statements)

References 244 publications

(311 reference statements)

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“…However, our findings now provide another mechanism through which general Hsp70 inhibitors might be effective anti-cancer agents; by inhibiting Hsc70-mediated regulation of MT stability. Indeed, compounds that alter MT dynamics are an area of extensive study and several are currently used in the clinic (51). Moreover, recent work even implicates tau in the pathogenesis and prognosis of cancer (52)(53)(54)(55)(56), further supporting this mechanistic link between tau, Hsc70 and MTs.…”

Section: Discussionmentioning

confidence: 95%

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

Fontaine¹,

Martin²,

Akoury³

et al. 2015

Human Molecular Genetics

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The pathological accumulation of abnormally hyperphosphorylated and aggregated tau, a neuronal microtubule (MT)-associated protein that functions to maintain MT stability, is implicated in a number of hereditary and sporadic neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease. Targeting tau for the treatment of these diseases is an area of intense interest and toward that end, modulation of cellular molecular chaperones is a potential therapeutic target. In particular, the constitutive Hsp70 isoform, Hsc70, seems highly interconnected with tau, preserving tau protein levels and synergizing with it to assemble MTs. But the relationship between tau and Hsc70, as well as the impact of this interaction in neurons and its therapeutic implications remain unknown. Using a human dominant negative Hsc70 that resembles isoform selective inhibition of this important chaperone, we found for the first time that Hsc70 activity is required to stimulate MT assembly in cells and brain. However, surprisingly, active Hsc70 also requires active tau to regulate MT assembly in vivo, suggesting that tau acts in some ways as a co-chaperone for Hsc70 to coordinate MT assembly. This was despite tau binding to Hsc70 as substrate, as determined biochemically. Moreover, we show that while chronic Hsc70 inhibition damaged MT dynamics, intermittent treatment with a small molecule Hsp70 inhibitor lowered tau in brain tissue without disrupting MT integrity. Thus, in tauopathies, where MT injury would be detrimental to neurons, the unique relationship of tau with the Hsc70 machinery can be exploited to deplete tau levels without damaging MT networks.

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Section: Discussionmentioning

confidence: 95%

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

Fontaine¹,

Martin²,

Akoury³

et al. 2015

Human Molecular Genetics

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“…Coupled with evidence of its aberrant expression levels in a wide range of tumors of neuronal and non-neuronal origin and disease aggressiveness and resistance to chemotherapy, β3-tubulin is thought to be a survival factor. Interaction between this tubulin isotype and VDAC was evoked to explain modulation of metabolic stress and mitochondrial functions in cancer cells (55). Future research will verify the preferential tubulin isotype interaction with VDAC in cells and potential modifications of these interactions under chemotherapeutic treatment.…”

Section: A Model Of the Tubulin Ctt-vdac Interaction -mentioning

confidence: 98%

Sequence diversity of tubulin isotypes in regulation of the mitochondrial voltage-dependent anion channel

Rostovtseva

Gurnev

Hoogerheide

et al. 2018

Journal of Biological Chemistry

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The microtubule protein tubulin is a heterodimer comprising / subunits, in which each subunit features multiple isotypes in vertebrates. For example, seven -tubulin and eight -tubulin isotypes in the human tubulin gene family vary mostly in the length and primary sequence of the disordered anionic C-terminal tails (CTTs). The biological reason for such sequence diversity remains a topic of vigorous enquiry. Here, we demonstrate that it may be a key feature of tubulin's role in regulation of the permeability of the mitochondrial outer membrane voltagedependent anion channel (VDAC). Using recombinant yeast /-tubulin constructs with -CTTs, -CTTs, or both from various human tubulin isotypes, we probed their interactions with VDAC reconstituted into planar lipid bilayers. A comparative study of the blockage kinetics revealed that either -CTTs or -CTTs block VDAC pore and that the efficiency of blockage by individual CTTs spans two orders of magnitude, depending on the CTT isotype.-Tubulin constructs, notably 3, blocked VDAC most effectively. We quantitatively describe these experimental results using a physical model that accounts only for the number and distribution of charges in the CTT, and not for the interactions between specific residues on the CTT and VDAC pore. Based on these results, we speculate that the effectiveness of VDAC regulation by tubulin depends on the predominant tubulin isotype in a cell. Consequently, the fluxes of ATP/ADP http://www.jbc.org/cgi

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“…More recently, we have also proven that expression of the NKG2D and DNAM-1 activating ligands MICA and PVR, is enhanced by immunomodulatory drugs (IMiDs) ( 24 ). It is well known that microtubules influence a variety of cell stress responses and act as coordinators of cell functions in response to stress ( 25 ). Recent work also suggests that induction of mitotic arrest by inhibitors of microtubule assembly can trigger DNA damage response pathways in mitotic-arrested cells ( [26][27][28] ).…”

Section: Introductionmentioning

confidence: 99%

p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells

et al. 2016

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The mechanisms that regulate the expression of the NKG2D and DNAM-1 activating ligands are only partially known, but it is now widely established that their expression is finely regulated at transcriptional, post-transcriptional and post-translational level, and involve numerous stress pathways depending on the type of ligand, stressor, and cell context.We show that treatment of Multiple Myeloma (MM) cells with sub-lethal doses of Vincristine (VCR), an anticancer drug that inhibits the assembly of microtubules, stimulates the expression of NKG2D and DNAM-1 activating ligands, rendering these cells more susceptible to NK cell-mediated killing. Herein, we focused our attention on the identification of the signaling pathways leading to de novo surface expression of ULBP-1, and to MICA and PVR upregulation on VCR-treated MM cells, both at protein and mRNA levels.We found that p38MAPK differentially regulates drug-dependent ligand upregulation at transcriptional and post-transcriptional level. More specifically, we observed that ULBP-1 expression is attributable to both increased transcriptional activity mediated by ATM-dependent p53 activation, and enhanced mRNA stability; while the p38-activated E2F1 transcription factor regulates MICA and PVR mRNA expression. All together, our findings reveal a previously unrecognized activity of VCR as anticancer agent, and indicate that in addition to its established ability to arrest cell growth, VCR can also modulate the expression of NKG2D and DNAM-1 activating ligand on tumor cells and thus promoting NK cell-mediated immunosurveillance.

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Microtubules and Their Role in Cellular Stress in Cancer

Cited by 328 publications

References 244 publications

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

Sequence diversity of tubulin isotypes in regulation of the mitochondrial voltage-dependent anion channel

p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells

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