LNX1 contributes to tumor growth by down-regulating p53 stability.

Abstract

The well-known tumor suppressor p53 inhibits the formation of various cancers by inducing cell cycle arrest and apoptosis. Although p53 mutations are commonly found in many cancers, p53 is functionally inactivated in tumor cells that retain wild-type p53. Here, we show that the ligand of numb protein X1 (LNX1) inhibited p53-dependent transcription by decreasing the half-life of p53. We generated LNX1 knockout (KO) cells in p53 wild-type cancer cells (A549, HCT116, and MCF7) using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 gene-editing system. LNX1 KO activated p53-dependent transcription by increasing the stability of p53. Moreover, lentivirus-mediated overexpression of LNX1 decreased p53 protein levels and inhibited p53-dependent transcription. LNX1 interacted with p53 and mouse double minute 2 (MDM2) and increased the ubiquitination of p53 in an MDM2-dependent manner. Finally, we demonstrated that LNX1 was required for efficient tumor growth both in cell culture and in a mouse tumor xenograft model. These results collectively indicated that LNX1 contributed to tumor growth by inhibiting p53-dependent signaling in p53 wild-type cancer cells.-Park, R., Kim, H., Jang, M., Jo, D., Park, Y.-I., Namkoong, S., Lee, J. I., Jang, I.-S., Park, J. LNX1 contributes to tumor growth by down-regulating p53 stability.

• Authors: Rackhyun Park, Hyunju Kim, Minsu Jang, Daum Jo, Yea-In Park, Sim Namkoong, Jin I Lee, Ik-Soon Jang, Junsoo Park
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 33 Issue 12 Pg. 13216-13227 (12 2019) ISSN: 1530-6860 [Electronic] United States
• PMID: 31533005 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Suppressor Protein p53
• LNX1 protein, human
• Proto-Oncogene Proteins c-mdm2
• Ubiquitin-Protein Ligases

Topics

• A549 Cells
• Animals
• Cell Proliferation (genetics, physiology)
• HCT116 Cells
• Humans
• MCF-7 Cells
• Mice
• Mice, Inbred BALB C
• Proto-Oncogene Proteins c-mdm2 (genetics, metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Xenograft Model Antitumor Assays