Evidence that P12, a specific variant of P16^INK4A, plays a suppressive role in human pancreatic carcinogenesis

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• 作者：Ming J. Poi ; Thomas J. Knobloch ; Chunhua Yuan ; Ming-Daw Tsai ; Christopher M. Weghorst ; Junan Li
• 关键词：P12 ; P16INK4A ; The INK4a-ARF locus ; Tumor suppression ; Pancreatic cancer
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2013
• 出版时间：28 June, 2013
• 年：2013
• 卷：436
• 期：2
• 页码：217-222
• 全文大小：774 K

文摘

The INK4a-ARF locus plays a central role in the development of pancreatic tumors as evidenced by the fact that up to 98 % of pancreatic tumor specimens harbored genetic alterations at the INK4a-ARF locus. Interestingly, in addition to the well-known P16^INK4A (P16) and P14ARF tumor suppressors, the INK4a-ARF locus in pancreas encodes another protein, P12, whose structure, function, and contributions to pancreatic carcinogenesis remain to be elucidated. In the current study, we demonstrated that over-expression of p12 in human pancreatic cancer cells led to cell arrest at the G1 phase and such cell cycle arrest was related to down-regulation of a number of oncogenes, such as c-Jun, Fos, and SEI1. Furthermore, unlike P16, P12 did not retain any cyclin-dependent kinase 4 (CDK4)-inhibitory activity. Instead, P12 exhibited a transactivating activity not found in P16. We also examined the genetic status of p12 in a cohort of 40 pancreatic tumor specimens and found that p12 alteration was prevalent in pancreatic tumors with an incidence of 70 % (28/40). These results support that P12 is a tumor suppressive protein distinct from P16, and its genetic inactivation is associated with pancreatic carcinogenesis.