Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar,
Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, PO Box 35, PC 123, Al Khoud, Sultanate of Oman.
Front Biosci (Elite Ed). 2020 Mar 1;12(2):223-236. doi: 10.2741/E868.
We have previously characterized the role of p16/Rb in coordinating the early events in UVB-irradiated skin. As an extension to this work, normal melanocytes and mutant p16-inducible melanoma cell models were employed to elucidate further the coordinated molecular mechanisms occurring during early UVB exposure. Our results showed that melanocytes expressed p16 only at a high UVB dose, with undetectable p53. The Bax/Bcl2 ratio increased at higher dose, indicating that the cells had selected apoptosis program. In the wt-p16 melanoma cells, while low UVB dose upregulated p16, the high dose suppressed it, and further abrogated Cdk6 but not Cdk4. Interestingly, while induction of mutant-p16 increased Cdk4, cdk6 and pRb proteins, UVB exposure did not affect this increase. More interestingly, p16 mutant cells increased their resistance to apoptosis at high UVB-dose, associated with decreased Bax and increased Bcl2 expression. Thus, mutant-p16 appears to dictate a deregulation of cell cycle and increased resistance to apoptosis in melanoma cells. Together, the data indicate a deregulation of p16INK4/Rb pathway as an early event in UVB-induced melanomagenesis.
我们之前已经描述了 p16/Rb 在协调 UVB 照射皮肤早期事件中的作用。作为这项工作的延伸，我们使用正常黑素细胞和突变 p16 诱导的黑素瘤细胞模型来进一步阐明在早期 UVB 暴露期间发生的协调分子机制。我们的结果表明，黑素细胞仅在高剂量的 UVB 下表达 p16，而检测不到 p53。Bax/Bcl2 比值在高剂量时增加，表明细胞已经选择了凋亡程序。在 wt-p16 黑素瘤细胞中，低剂量的 UVB 上调了 p16，但高剂量的 UVB 抑制了 p16 的表达，并进一步阻断了 Cdk6，但没有阻断 Cdk4。有趣的是，虽然突变型 p16 的诱导增加了 Cdk4、cdk6 和 pRb 蛋白，但 UVB 暴露并没有影响这种增加。更有趣的是，p16 突变细胞在高剂量 UVB 下增加了对细胞凋亡的抵抗力，与 Bax 减少和 Bcl2 表达增加有关。因此，突变型 p16 似乎导致黑素瘤细胞中的细胞周期失调和对细胞凋亡的抵抗力增加。总之，数据表明 p16INK4/Rb 通路的失调是 UVB 诱导黑素瘤发生的早期事件。
