The TACC proteins: TACC-ling microtubule dynamics and centrosome function

Peset, Isabel; Vernos, Isabelle

doi:10.1016/j.tcb.2008.06.005

Cited by 144 publications

(181 citation statements)

References 75 publications

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“…TACC3 is an Epoinducible member of the TACC family (18), all of which share an approximately 200 residue dimeric C-terminal coiled-coil domain that interacts with numerous transcription factors and chromatin-modifying proteins (Fig. 1A) (19). Here we identify the molecular basis for TACC3 regulation of HIF transactivation, mediated by a direct interaction with ARNT PAS-B that utilizes an interface shared with TRIP230 and CoCoA.…”

Section: Transcriptional Coactivators | Protein/protein Interactions mentioning

confidence: 82%

Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B

Partch

Gardner

2011

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxia-inducible factor (HIF) is the key transcriptional effector of the hypoxia response in eukaryotes, coordinating the expression of genes involved in oxygen transport, glycolysis, and angiogenesis to promote adaptation to low oxygen levels. HIF is a basic helixloop-helix (bHLH)-PAS (PER-ARNT-SIM) heterodimer composed of an oxygen-labile HIF-α subunit and a constitutively expressed aryl hydrocarbon receptor nuclear translocator (ARNT) subunit, which dimerize via basic helix-loop-helix and PAS domains, and recruit coactivators via HIF-α C-terminal transactivation domains. Here we demonstrate that the ARNT PAS-B domain provides an additional recruitment site by binding the coactivator transforming acidic coiled-coil 3 (TACC3) in a step necessary for transcriptional responses to hypoxia. Structural insights from NMR spectroscopy illustrate how this PAS domain simultaneously mediates interactions with HIF-α and TACC3. Finally, mutations on ARNT PAS-B modulate coactivator selectivity and target gene induction by HIF in vivo, demonstrating a bifunctional role for transcriptional regulation by PAS domains within bHLH-PAS transcription factors. transcriptional coactivators | protein/protein interactions | bifunctional interactionsA ryl hydrocarbon receptor nuclear translocator (ARNT) is the obligate heterodimeric partner for the basic helix-loop-helix (bHLH)-PAS (PER-ARNT-SIM) proteins aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor-α (HIF-α), which serve as environmental sensors for xenobiotics and hypoxia, respectively (1). bHLH-PAS heterodimers are dependent on intersubunit contacts between the basic bHLH and tandem PAS domains (2-4). The second of two PAS domains, PAS-B, plays a critical role in maintaining the stability of this complex, given that mutations in HIF-2α PAS-B disrupt HIF-α/ARNT interactions and decrease transactivation in vivo (3, 4). Therefore, our current model of bHLH-PAS heterodimer architecture is based on nucleation of the core transcription factor complex by bHLH and PAS domains, leaving C-terminal transactivation domains (TADs) to recruit coactivator proteins that are required for gene regulation (Fig. 1A).Further study of HIF TADs reveals that not all are essential for HIF function. In particular, deletion of the putative ARNT C-terminal TAD has a minimal effect on transactivation of endogenous targets (5-7), whereas deletion of the two HIF-α TADs (N-TAD and C-TAD) eliminates hypoxia-induced transactivation (8). Consequently, study of HIF transcriptional regulation has focused on the HIF-α TADs, identifying the C-TAD as the primary site of recruitment for p300/CBP (9) and the N-TAD as a determining factor in the distinctive profiles of target gene induction by . Selectivity is mediated in part by the recruitment of different coactivators by the N-TADs of the two HIF-α isoforms, building on an emerging theme that transcriptional coregulators and promoter context influence the specificity of gene induction by transcription factors (11,12). Domain-swapping studies have shown tha...

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Section: Transcriptional Coactivators | Protein/protein Interactions mentioning

confidence: 82%

Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B

Partch

Gardner

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…6 D-TACC associates with and stabilizes both the plus-and minus-ends of astral and spindle microtubules. 120 Mammals possess three TACC proteins, one of which is crucial for clustering. 92 TACC3 localizes to the centrosome and spindle microtubules during mitosis and, like D-TACC, it regulates the length and number of spindle microtubules.…”

Section: Surviving With Surplus: Managing Supernumerary Centrosomes Bmentioning

confidence: 99%

“…92 TACC3 localizes to the centrosome and spindle microtubules during mitosis and, like D-TACC, it regulates the length and number of spindle microtubules. 120 TACC proteins recruit the MAP ch-TOG to the centrosome where they form a complex; 118,120 however, ch-TOG promotes polymerization of microtubule plus-ends and antagonizes their depolymerization by MCAK. 121 TACC3 and ch-TOG are required for clustering in human breast BT549 and prostate cancer PC3 cells.…”

Section: Surviving With Surplus: Managing Supernumerary Centrosomes Bmentioning

confidence: 99%

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

2012

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Nearly a century ago, cell biologists postulated that the chromosomal aberrations blighting cancer cells might be caused by a mysterious organelle-the centrosome-that had only just been discovered. For years, however, this enigmatic structure was neglected in oncologic investigations and has only recently reemerged as a key suspect in tumorigenesis. A majority of cancer cells, unlike healthy cells, possess an amplified centrosome complement, which they manage to coalesce neatly at two spindle poles during mitosis. This clustering mechanism permits the cell to form a pseudo-bipolar mitotic spindle for segregation of sister chromatids. On rare occasions this mechanism fails, resulting in declustered centrosomes and the assembly of a multipolar spindle. Spindle multipolarity consigns the cell to an almost certain fate of mitotic arrest or death. The catastrophic nature of multipolarity has attracted efforts to develop drugs that can induce declustering in cancer cells. Such chemotherapeutics would theoretically spare healthy cells, whose normal centrosome complement should preclude multipolar spindle formation. In search of the 'Holy Grail' of nontoxic, cancer cell-selective, and superiorly efficacious chemotherapy, research is underway to elucidate the underpinnings of centrosome clustering mechanisms. Here, we detail the progress made towards that end, highlighting seminal work and suggesting directions for future research, aimed at demystifying this riddling cellular tactic and exploiting it for chemotherapeutic purposes. We also propose a model to highlight the integral role of microtubule dynamicity and the delicate balance of forces on which cancer cells rely for effective centrosome clustering. Finally, we provide insights regarding how perturbation of this balance may pave an inroad for inducing lethal centrosome dispersal and death selectively in cancer cells.

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“…However, while manipulation of TACC3 resulted in abnormal MT dynamics in Xenopus cells [Nwagbara et al, 2014], it did not significantly alter MT dynamics in human RPE1 cells [Gutierrez‐Caballero et al, 2015]. One possible explanation for this difference is that it has been reported that Xenopus only contains a single member, TACC3/Maskin [Ha et al, 2013; Peset and Vernos, 2008], while humans possess three members [Gergely et al, 2000]. Thus, there might be TACC functional redundancy in human cells that is not present within organisms possessing only a single family member.…”

Section: Introductionmentioning

confidence: 99%

Xenopus TACC1 is a microtubule plus‐end tracking protein that can regulate microtubule dynamics during embryonic development

et al. 2015

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Microtubule plus‐end dynamics are regulated by a family of proteins called plus‐end tracking proteins (+TIPs). We recently demonstrated that the transforming acidic coiled‐coil (TACC) domain family member, TACC3, can function as a +TIP to regulate microtubule dynamics in Xenopus laevis embryonic cells. Although it has been previously reported that TACC3 is the only TACC family member that exists in Xenopus, our examination of its genome determined that Xenopus, like all other vertebrates, contains three TACC family members. Here, we investigate the localization and function of Xenopus TACC1, the founding member of the TACC family. We demonstrate that it can act as a +TIP to regulate microtubule dynamics, and that the conserved C‐terminal TACC domain is required for its localization to plus‐ends. We also show that, in Xenopus embryonic mesenchymal cells, TACC1 and TACC3 are each required for maintaining normal microtubule growth speed but exhibit some functional redundancy in the regulation of microtubule growth lifetime. Given the conservation of TACC1 in Xenopus and other vertebrates, we propose that Xenopus laevis is a useful system to investigate unexplored cell biological functions of TACC1 and other TACC family members in the regulation of microtubule dynamics. © 2015 The Authors. Cytoskeleton, Published by Wiley Periodicals, Inc.

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The TACC proteins: TACC-ling microtubule dynamics and centrosome function

Cited by 144 publications

References 75 publications

Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B

Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

Xenopus TACC1 is a microtubule plus‐end tracking protein that can regulate microtubule dynamics during embryonic development

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