Requirements for Aurora-A in tissue regeneration and tumor development in adult mammals.
Aurora-A is a kinase involved in the formation and maturation of the mitotic spindle and chromosome segregation. This kinase is frequently overexpressed in human cancer, and its activity may confer resistance to antitumoral drugs such as Taxol. Inhibition of Aurora-A results in mitotic defects, and this kinase is considered as an attractive therapeutic target for cancer. Nevertheless, the specific requirements for this kinase in adult mammalian tissues remain unclear. Conditional genetic ablation of Aurora-A in adult tissues results in polyploid cells that display a DNA-damage-like response characterized by the upregulation of p53 and the cell-cycle inhibitor p21(Cip1). This is accompanied by apoptotic, differentiation, or senescence markers in a tissue-specific manner. Therapeutic elimination of Aurora-A prevents the progression of skin and mammary gland tumors. However, this is not due to significant levels of apoptosis or senescence, but because Aurora-A-deficient tumors accumulate polyploid cells with limited proliferative potential. Thus, Aurora-A is required for tumor formation in vivo, and the differential response observed in various tissues might have relevant implications in current therapeutic strategies aimed at inhibiting this kinase in the treatment of human cancer.
Authors' Affiliations: Cell Division and Cancer Group; Histopathology Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; and Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.
Ignacio
I
Pérez de Castro
Cristina
C
Aguirre-Portolés
Gonzalo
G
Fernández-Miranda
Marta
M
Cañamero
Dale O
DO
Cowley
Terry
T
Van Dyke
Marcos
M
Malumbres
D000818:Animals; D064096:Aurora Kinase A / Q000235:genetics / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics*; D012038:Regeneration / Q000235:genetics*
D064096:Aurora Kinase A