The tumor suppressor p16(INK4a) gene is a regulator of apoptosis induced by ultraviolet light and cisplatin.
p16(INK4a) (hereafter referred to as p16), a major cyclin-dependent kinase (CDK) inhibitor, is the product of a tumor-suppressor gene that has been found inactivated in different cancer types. In the present study, we sought to investigate the role of p16 in apoptosis induced by ultraviolet light (the most important etiological cause of skin cancer) and cisplatin (an anticancer DNA damaging agent). It is clearly shown that p16-compromised osteosarcoma U2OS cell line and p16-/- mouse embryo fibroblasts are sensitive to UV-induced apoptosis, as compared to their respective isogenic p16-expressing cells (EH1, EH2) and p16 +/+, indicating that p16 protects cells from undergoing apoptosis in response to UV light. Importantly, this reduction in UV-mediated apoptosis was associated with downregulation of the proapoptotic Bax protein, with no effect on Bcl-2 expression, suggesting that this antiapoptotic role of p16 is mediated via the intrinsic-mitochondrial pathway. On the other hand, p16 sensitized cells to cisplatin-mediated apoptosis through Bcl-2 decline. Interestingly, only proliferating but not G1-arrested EH1 cells underwent apoptosis in response to the anticancer drug. These novel findings provide further insight into the role of p16 in carcinogenesis, and has potential implications for future therapy strategies.
Al-Mohanna
Mai A
MA
King Faisal Specialist Hospital and Research Center, BMR, MBC # 03, PO Box 3354, Riyadh 11211, Saudi Arabia.
Manogaran
Pulicat S
PS
Al-Mukhalafi
Zuha
Z
A Al-Hussein
Khaled
K
Aboussekhra
Abdelilah
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002945:Cisplatin; D004249:DNA Damage; D004260:DNA Repair; D019942:Genes, p16 / Q000502:physiology*; D006801:Humans; D051379:Mice; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D014466:Ultraviolet Rays; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D002945:Cisplatin