The TACC proteins: TACC-ling microtubule dynamics and centrosome function.
ABSTRACT A major quest in cell biology is to understand the molecular mechanisms underlying the high plasticity of the microtubule network at different stages of the cell cycle, and during and after differentiation. Initial reports described the centrosomal localization of proteins possessing transforming acidic coiled-coil (TACC) domains. This discovery prompted several groups to examine the role of TACC proteins during cell division, leading to indications that they are important players in this complex process in different organisms. Here, we review the current understanding of the role of TACC proteins in the regulation of microtubule dynamics, and we highlight the complexity of centrosome function.
- SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Accurate chromosome segregation requires timely bipolar spindle formation during mitosis. The transforming acidic coiled-coil (TACC) family proteins and the ch-TOG family proteins are key players in bipolar spindle formation. They form a complex to stabilize spindle microtubules, mainly dependent of their localization to the centrosome (the spindle pole body/SPB in yeast). The molecular mechanism underlying the targeting of the TACC-ch-TOG complex to the centrosome remains unclear. Here, we show that the fission yeast Schizosacchromyces pombe TACC ortholog alp7p is recruited to the SPB by csi1p. The csi1p interacting region lies within the conserved TACC domain of alp7p while the carboxyl-terminal domain of csi1p is responsible for interacting with alp7p. Compromised interaction between csi1p and alp7p impairs the localization of alp7p to the SPB during mitosis, thus delaying bipolar spindle formation and leading to anaphase B lagging chromosomes. Hence, our study establishes that csi1p serves as a linking molecule tethering spindle stabilizing factors to the SPB for promoting bipolar spindle assembly.Molecular Biology of the Cell 07/2014; · 4.55 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Microtubule plus-end dynamics are regulated by a conserved family of proteins called 'plus-end-tracking proteins' (+TIPs). Yet, it is still unclear how various +TIPs interact with each other and with plus-ends to control microtubule behavior. The centrosome-associated protein TACC3, a member of the transforming acidic coiled coil (TACC) domain family, has been previously implicated in regulating several aspects of microtubule dynamics. However, TACC3 has not been shown to function as a +TIP in vertebrates. Here, we show that TACC3 promotes axon outgrowth and regulates microtubule dynamics by increasing microtubule plus-end velocities in vivo. We also demonstrate that TACC3 acts as a +TIP in multiple embryonic cell types, and that this requires the conserved C-terminal TACC domain. Using high-resolution live-imaging data of tagged +TIPs, we reveal that TACC3 localizes to the extreme microtubule plus-end, where it lies distal to the microtubule polymerization marker, EB1, and directly overlaps with the microtubule polymerase, XMAP215. TACC3 also plays a role in regulating XMAP215 stability and localizing XMAP215 to microtubule plus-ends. Together, our results implicate TACC3 as a +TIP that functions with XMAP215 to regulate microtubule plus-end dynamics.Molecular Biology of the Cell 09/2014; 25(21). · 4.55 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The centrosome regulates diverse cellular processes, including cell proliferation and differentiation. TACC3, a member of the human transforming acidic coiled-coil protein family, is a key centrosomal protein that is up-regulated in many cancers. Previous studies have demonstrated that TACC3 is essential for the survival of vertebrates and is involved in cell cycle regulation in human cells. However, the details of the underlying mechanisms in its cell cycle regulatory activity remain poorly understood. In this study, we showed that suppression of TACC3 expression induced G1 cell cycle arrest and triggered cell death in human cells. TACC3 depletion-induced G1 arrest and cell death were significantly reduced in cells either lacking p53 or with pharmacologically-inhibited p38, indicating that G1 arrest and cell death induction both require p53 and p38. TACC3 depletion up-regulated the levels of p53 and p21 and induced the accumulation of p53 both in the nucleus and at the centrosome. Interestingly, TACC3 depletion led to the activation of p38 and stimulated the recruitment of activated p38 to the centrosome. Depletion of TACC3 up-regulated the phosphorylation of p53 at Serine 33, a site known to be phosphorylated by p38 under cellular stress and further induced the accumulation of phosphorylated p53 to the centrosome. Loss of TACC3 affected centrosome integrity by disrupting the localization of components of the γ-tubulin ring complex at the centrosome. The results demonstrate that TACC3 depletion induces G1 arrest and cell death by activating p38–p53–p21 signaling and triggering a centrosome-mediated cellular stress response.European Journal of Cell Biology 01/2015; 94(2). · 3.70 Impact Factor