Unconventional Functions of Mitotic Kinases in Kidney Tumorigenesis

Abstract

Human tumors exhibit a variety of genetic alterations, including point mutations, translocations, gene amplifications and deletions, as well as aneuploid chromosome numbers. For carcinomas, aneuploidy is associated with poor patient outcome for a large variety of tumor types, including breast, colon, and renal cell carcinoma. The Renal cell carcinoma (RCC) is a heterogeneous carcinoma consisting of different histologic types. The clear renal cell carcinoma (ccRCC) is the most common subtype and represents 85% of the RCC. Central to the biology of the ccRCC is the loss of function of the Von Hippel-Lindau gene, but is also associated with genetic instability that could be caused by abrogation of the cell cycle mitotic spindle checkpoint and may involve the Aurora kinases, which regulate centrosome maturation. Aneuploidy can also result from the loss of cell-cell adhesion and apical-basal cell polarity that also may be regulated by the mitotic kinases (polo-like kinase 1, casein kinase 2, doublecortin-like kinase 1, and Aurora kinases). In this review, we describe the "non-mitotic" unconventional functions of these kinases in renal tumorigenesis.

Keywords: Aurora-A kinase; kidney; mitotic kinases; non-mitotic functions; tumorigenesis.

Figure 1

Overexpressed CK2 induces HIFα accumulation through VHL-dependent or independent mechanisms. CK2 can down-regulate VHL expression at the transcriptional level (i) by phosphorylating HDACs (125) as well as at post-translational level and (ii) by destabilizing phosphorylation in the NH₂-terminal acidic domain of VHL (126). In the latter case, CK2-induced destabilization of VHL also results in p53 inactivation, which can no longer inhibit HIFα transcription (iii); (126, 127). Finally, (iv) cdc37 phosphorylation by CK2 allows HSP90/cdc37 dimer formation and the subsequent interaction of this complex with HIF-1α, which is essential for its cellular stability (128, 129).

Figure 2

Non-mitotic functions of the kinase Aurora-A: different biological processes as cilia resorption, cell polarity or cell migration are influenced by Aurora-A upstream mitosis, which can later affect chromosome segregation.