Ionizing radiation inhibits the PLK cell cycle gene in a G2 checkpoint-dependent manner.
Tumor cell cycle arrest at the cell cycle G2/M boundary after ionizing radiation involves inhibition of the Polo-like kinase 1 (Plk1). We recently found that the mechanism comprised repression of its gene, PLK, mediated by the tumor-suppressor protein BRCA1. In the present study we examined the regulatory responses on PLK and cell cycle phases in breast carcinoma cell lines exposed to various modes of therapeutic irradiation. The tumor cells, harboring different DNA damage checkpoint defects, were irradiated with either a single dose of 8.0 Gy or fractionated doses accumulating to 8.0 Gy. In the BRCA1-/- HCC1937 cell line both radiation regimens caused moderate repression of PLK mRNA expression, whereas the reconstituted wild-type (wt) BRCA1 genotype of the HCC1937/BRCA1wt cell line was associated with significant down-regulation of PLK mRNA expression after irradiation. In contrast to the HCC1937 cell lines, the MCF7/LCC2 cells displayed the characteristic wt TP53 constitution of persistent, radiation-induced CDKN1A mRNA expression (encoding the G1 cell cycle inhibitor p21(Waf1/Cip1/Sdi1)). The regulatory effects on PLK in the MCF7/LCC2 cells, however, were identical to those in the HCC1937/BRCA1wt cell line. Moreover, whereas neither HCC1937 cell line displayed G1/S cell cycle arrest after irradiation but, instead, an apparent accumulation of G2/M-phase cells, the radiation-induced delay at the G1/S boundary seemed to be superior to arrest at the G2/M transition in the MCF7/LCC2 cell line. Since the down-regulation of PLK mRNA expression by ionizing radiation was identical in the wt TP53 MCF7/LCC2 cell line and the TP53-mutated BRCA1-/- HCC1937 cell line reconstituted with wt BRCA1, we conclude that this regulatory effect solely requires an intact G2 checkpoint effector mechanism.
Ree
Anne Hansen
AH
Department of Tumor Biology, The Norwegian Radium Hospital, 0310 Oslo, Norway. a.h.ree@labmed.uio.no
Bratland
Ase
A
Solberg Landsverk
Kirsti
K
Fodstad
Oystein
O
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D016195:G2 Phase / Q000235:genetics / Q000528:radiation effects*; D006801:Humans; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000528:radiation effects; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000097869:Polo-Like Kinase 1