PAR, a protein involved in the cell cycle, is functionally related to chromosomal passenger proteins

Abstract

Prostate androgen regulated (PAR) protein is a 148 amino acid polypeptide ubiquitously expressed in normal cells and overexpressed in many malignancies. Manipulation of PAR mRNA in DU145 and NIH3T3 cells indicated that its expression level is an important determinant of cell in vitro proliferation, clonogenicity in soft agar and in vivo tumorigenicity. In this study, we showed that PAR is a short-lived protein with a peak in G2/M phase. Using immunofluorescent antibodies we showed that PAR moves from centrosomes in prophase and metaphase to spindle midzone in anaphase, and concentrates to midbody in telophase and cytokinesis. During mitosis a fraction of PAR can also be detected in the cytoplasm. PAR pattern of expression and its dynamic localization suggested a functional relationship to chromosomal passenger proteins (CPP). This protein colocalized with Aurora A at centrosomes in metaphase, and with survivin at midbody in telophase and cytokinesis. It also formed complexes with Aurora A, and with survivin, Aurora B and INCENP. In addition, PAR increased Aurora B kinase activity on histone H3. The decreased PAR levels in DU145 cells resulted in defects in centrosome segregation, in failed cytokinesis and chromosome alignment, and in increased number of apoptotic cells, polyploidy and aberrant mitosis. It is known that such defects could lead to genomic instability and tumorigenesis. In this study we also confirm our earlier findings that PAR is overexpressed in many tumors. Due to its involvement in cell cycle and its overexpression in several human cancers PAR could represent an attractive target for therapeutic intervention.