Int J Biol Sci 2018; 14(2):165-177. doi:10.7150/ijbs.23477 This issue Cite

Research Paper

Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency

Xiaoyu Si1,2*, Chihao Shao1*, Jing Li1,3, Shuting Jia1, Wenru Tang1, Jihong Zhang1, Julun Yang3, Xiaoming Wu1✉, Ying Luo1,2,4✉

1. Lab of Molecular Genetics of Aging & Tumor, Faculty of Medicine, Kunming University of Science & Technology, 727 South Jing Ming Road, Chenggong County, Kunming, Yunnan Province, China, 650500
2. College of Biological Engineering, Qilu University of Technology (Shandong Academy of Sciences), 3501 University Road, Changqing County, Jinan, Shandong Province, China, 250353
3. Faculty of Environmental Science and Engineering, Kunming University of Science & Technology, 727 South Jing Ming Road, Chenggong County, Kunming, Yunnan Province, China, 650500
4. Department of Pathology, Kunming General Hospital, 212 Daguan Road, Kunming, Yunnan Province, China, 650032
5. Yunnan Provincial Institute of Digestive Disease
*These authors contribute equally to this work.

Citation:
Si X, Shao C, Li J, Jia S, Tang W, Zhang J, Yang J, Wu X, Luo Y. Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency. Int J Biol Sci 2018; 14(2):165-177. doi:10.7150/ijbs.23477. https://www.ijbs.com/v14p0165.htm
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Abstract

Graphic abstract

Werner syndrome (WS) is a rare autosomal recessive progeria disease with genetic instability/cancer predisposition, thus a good model in understanding aging related carcinogenesis. Telomere dysfunction induced cellular senescence is essential in the manifestation of the WS phenotype. Our previous data has shown that p21 (encoded by Cdkn1a gene) could induce cellular senescence and suppress cellular growth of ALT (alternative lengthening of telomere) tumors derived from WS, suggested that p21 might play a key role in maintaining senescence of WS cells.

To confirm the role of p21 in suppressing telomere dysfunction induced tumorigenesis, we overexpressed dominant negative protein TRF2ΔBΔM in p21-/- mouse embryonic fibroblasts (MEFs). To further stress the cell, we crossed Wrn-/- mice with p21-/- mice to obtained p21-/-Wrn-/- MEFs, and overexpressed TRF2ΔBΔM in these MEFs to induce telomere dysfunction similar to that in WS cells. Our data showed that, in the context of p21-/- TRF2ΔBΔM, loss of p21 function rescued cellular senescence, and induced p53 mutation, but did not induce tumorigenesis. However, in the set of p21-/-Wrn-/-TRF2ΔBΔM, loss of p21 function induced p53 mutation and tumorigenesis.

To further verify the role of p21 in suppressing telomere dysfunction related tumorigenesis, we knocked down p21 in non-tumorigenic immortalized cells derived from WS MEFs (mTerc-/-Wrn-/-), and found that loss of p21 could induce ALT tumorigenesis, which displayed typical smear pattern of telomere length and arc-shaped telomeric DNA. In another hand, recovering telomerase activity in these MEFs could also induce tumorigenesis without affecting p21 expression level. Together our data suggested that p21 controlled cell cycle regulation played an essential role in suppressing telomere dysfunction-related tumorigenesis. These data also suggested that the genetic context is essential in determining the role of p21 in cancer prevention. Therefore, targeting p21 in the treatment of human degenerative diseases would require a personalized genetic background screen.

Keywords: p21, Wrn, telomere dysfunction, senescence, tumorigenesis


Citation styles

APA
Si, X., Shao, C., Li, J., Jia, S., Tang, W., Zhang, J., Yang, J., Wu, X., Luo, Y. (2018). Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency. International Journal of Biological Sciences, 14(2), 165-177. https://doi.org/10.7150/ijbs.23477.

ACS
Si, X.; Shao, C.; Li, J.; Jia, S.; Tang, W.; Zhang, J.; Yang, J.; Wu, X.; Luo, Y. Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency. Int. J. Biol. Sci. 2018, 14 (2), 165-177. DOI: 10.7150/ijbs.23477.

NLM
Si X, Shao C, Li J, Jia S, Tang W, Zhang J, Yang J, Wu X, Luo Y. Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency. Int J Biol Sci 2018; 14(2):165-177. doi:10.7150/ijbs.23477. https://www.ijbs.com/v14p0165.htm

CSE
Si X, Shao C, Li J, Jia S, Tang W, Zhang J, Yang J, Wu X, Luo Y. 2018. Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency. Int J Biol Sci. 14(2):165-177.

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