Chk2 regulates transcription-independent p53-mediated apoptosis in response to DNA damage.
The tumor suppressor protein p53 plays a central role in the induction of apoptosis in response to genotoxic stress. The protein kinase Chk2 is an important regulator of p53 function in mammalian cells exposed to ionizing radiation (IR). Cells derived from Chk2-deficient mice are resistant to the induction of apoptosis by IR, and this resistance has been thought to be a result of the defective transcriptional activation of p53 target genes. It was recently shown, however, that p53 itself and histone H1.2 translocate to mitochondria and thereby induces apoptosis in a transcription-independent manner in response to IR. We have now examined whether Chk2 also regulates the transcription-independent induction of apoptosis by p53 and histone H1.2. The reduced ability of IR to induce p53 stabilization in Chk2-deficient thymocytes was associated with a marked impairment of p53 and histone H1 translocation to mitochondria. These results suggest that Chk2 regulates the transcription-independent mechanism of p53-mediated apoptosis by inducing stabilization of p53 in response to IR.
Chen
Chen
C
Department of Geriatric Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522, Japan.
Shimizu
Shigeomi
S
Tsujimoto
Yoshihide
Y
Motoyama
Noboru
N
D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000502:physiology*; D004307:Dose-Response Relationship, Radiation; D005786:Gene Expression Regulation / Q000502:physiology / Q000528:radiation effects; D006657:Histones / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000502:physiology / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D011829:Radiation Dosage; D011839:Radiation, Ionizing; D013950:Thymus Gland / Q000502:physiology* / Q000528:radiation effects*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D006657:Histones; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases