Subcellular localization and nucleocytoplasmic transport of the chromosomal passenger proteins before nuclear envelope breakdown

Abstract

As mitosis progresses, the chromosomal passenger proteins (CPPs) Survivin, Aurora B, INCENP and Borealin dynamically colocalize to mitotic structures. Chromosomal passenger proteins are already expressed during G2, whereas the nuclear envelope is only disassembled at the end of prophase. However, the mechanisms that modulate their nucleocytoplasmic localization before nuclear envelope breakdown (NEB) are poorly characterized. Using epitope-tagged proteins, we show that Aurora B, like Survivin, undergoes CRM1-mediated nucleocytoplasmic shuttling, although both proteins lack identifiable 'classical' nuclear transport signals. On the other hand, INCENP resides more stably in the nucleus and contains multiple nuclear localization signals. Finally, Borealin was detected in the nucleolus and the cytoplasm, but its cytoplasmic localization is not directly regulated by CRM1. Coexpression experiments indicate that the nuclear localization of Aurora B, but not of Survivin, is modulated by INCENP and that Survivin prevents the nucleolar accumulation of Borealin. Our data reveal that, in contrast to their closely related localization during mitosis, the nucleocytoplasmic localization of the CPPs before NEB is largely unrelated. Furthermore, the specific effect of INCENP and Survivin on the localization of Aurora B and Borealin, respectively, suggests that different complexes of CPPs may exist not only during mitosis, as recently reported, but also before NEB.

Expression of HuR, COX-2, and survivin in lung cancers; cytoplasmic HuR stabilizes cyclooxygenase-2 in squamous cell carcinomas

“…functions. [15][16][17][18] Nuclear export signals (NES) are leucine-rich, interact with the export receptor Crm1 in the nucleus, and depend on the RanGTP/ GDP axis, which control the Crm1/substrate interaction. 16 Preferential nuclear survivin was indeed found to be a favorable predictor for various tumor types, although some reports consider nuclear survivin to be associated with poor survival.…”

“…14 Recent evidence shows that the direct interaction of survivin with the nuclear export receptor Crm1 is critically involved in the intracellular localization and cancer-relevant functions of survivin. [15][16][17][18] Survivin is also able to bind caspases, thus preventing their activation ( Figure 1). 19 Suppression of survivin expression leads to increased caspase-3 activation and apoptosis, as well as mitosis deregulation and sensitization to anticancer drugs.…”

Regulation of Greatwall kinase by protein stabilization and nuclear localization

“…Similarly, dynamic subcellular localization of Plk1 and Aurora A has been shown to regulate their functions during mitotic progression. [30][31][32][33] One mechanism to regulate the nuclear localization of a protein is through association with the importin family members. Importin is typically composed of 2 subunits, importin a and importin b.…”

Identification of Myb-binding Protein 1A (MYBBP1A) as a Novel Substrate for Aurora B Kinase

“…In early mitosis, the CPC promotes correct chromosome alignment and is responsible for the displacement of HP-1 from mitotic chromosomes by modifying histone H3, whereas at the end of mitosis, CPC regulates proper completion of cytokinesis (23,24). The non-enzymatic components of this complex control the targeting, enzymatic activity, and stability of Aurora B kinase (25)(26)(27)(28), and although the major role of CPC is in mitosis, its components are already expressed earlier in the cell cycle, when different complexes of chromosomal passenger proteins may exist (29). Recently, for example, Aurora B, INCENP, and Borealin, but not survivin, have been reported to be components of the nucleolar proteome (30).…”