Loss of p15/Ink4b accompanies tumorigenesis triggered by complex DNA double-strand breaks.
DNA double-strand breaks (DSBs) are the most deleterious lesion inflicted by ionizing radiation. Although DSBs are potentially carcinogenic, it is not clear whether complex DSBs that are refractory to repair are more potently tumorigenic compared with simple breaks that can be rapidly repaired, correctly or incorrectly, by mammalian cells. We previously demonstrated that complex DSBs induced by high-linear energy transfer (LET) Fe ions are repaired slowly and incompletely, whereas those induced by low-LET gamma rays are repaired efficiently by mammalian cells. To determine whether Fe-induced DSBs are more potently tumorigenic than gamma ray-induced breaks, we irradiated 'sensitized' murine astrocytes that were deficient in Ink4a and Arf tumor suppressors and injected the surviving cells subcutaneously into nude mice. Using this model system, we find that Fe ions are potently tumorigenic, generating tumors with significantly higher frequency and shorter latency compared with tumors generated by gamma rays. Tumor formation by Fe-irradiated cells is accompanied by rampant genomic instability and multiple genomic changes, the most interesting of which is loss of the p15/Ink4b tumor suppressor due to deletion of a chromosomal region harboring the CDKN2A and CDKN2B loci. The additional loss of p15/Ink4b in tumors derived from cells that are already deficient in p16/Ink4a bolsters the hypothesis that p15 plays an important role in tumor suppression, especially in the absence of p16. Indeed, we find that reexpression of p15 in tumor-derived cells significantly attenuates the tumorigenic potential of these cells, indicating that p15 loss may be a critical event in tumorigenesis triggered by complex DSBs.
Camacho
Cristel V
CV
Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Mukherjee
Bipasha
B
McEllin
Brian
B
Ding
Liang-Hao
LH
Hu
Burong
B
Habib
Amyn A
AA
Xie
Xian-Jin
XJ
Nirodi
Chaitanya S
CS
Saha
Debabrata
D
Story
Michael D
MD
Balajee
Adayabalam S
AS
Bachoo
Robert M
RM
Boothman
David A
DA
Burma
Sandeep
S
D000818:Animals; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000209:etiology*
C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16