Abstract 2160: Tumor suppressor p53 down-regulates programmed cell death protein 4 (PDCD4) expression

Abstract

Programmed Cell Death Protein 4 (PDCD4), a well-known tumor suppressor, acts to inhibit translation initiation and cap-dependent translation by inhibiting the helicase activity of EIF4A. EIF4A tends to target mRNAs with structured 5'-UTR. PDCD4 can also prevent tumorigenesis by inhibiting tumor promoter-induced neoplastic transformation, and studies indicate that PDCD4 may inhibit translation of certain mRNAs via directly binding. A previous study has demonstrated that PDCD4 inhibits translation of p53 mRNA and treatment with DNA-damaging agents down-regulates PDCD4 expression but activates p53 expression. The study further demonstrated that treatment with DNA-damaging agents resulted in down-regulation of PDCD4 expression and an increase in p53 expression, suggesting a potential mechanism in which p53 regulates expression of Pdcd4. However, whether p53 directly regulates PDCD4 remains unknown. Herein, we demonstrate for the first time that p53 regulates PDCD4 expression. First, we found that overexpression of p53 in p53-null cells (H1299 and Saos2 cells) decreased PDCD4 protein level. Secondly, p53 dose-dependently decreased PDCD4 promoter activity in gene reporter assays. Moreover, we demonstrated that mutations on p53 (R273H: contact mutant, hotspot and R175H: conformational mutant, hotspot) abolished p53-mediated PDCD4 repression. Furthermore, using Tet-on expression system, PDCD4 protein level was decreased when WT p53, but not hotspot mutants of p53, was expressed in H1299 cells. Finally, mutations on DNA-binding domain, but not C-terminal regulatory domain, of p53 disrupted p53-mediated PDCD4 repression. Taken together, our results suggest that p53 functions as a novel regulator of PDCD4 and the relationship between of p53 and PDCD4 may be involved in tumor development and progression. Citation Format: Wei-Hsiung Yang, Andrew P. George, William H. Yang, Chiung-Min Wang, Richard H. Yang. Tumor suppressor p53 down-regulates programmed cell death protein 4 (PDCD4) expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2160.

Author Index

“…Ho, D, 2844 Hoang, HQ, 1008 Hobbs, RG, 3346 Hodgkins, R, 2800 Hodnik, N, 2458 Hodoroaba, VD, 2002, 2250, 3302 Hoefer, N, 1522 Hoenger, A, 850 Hoffman, A, 2910, 3380 Hofmann, F, 2648 Hogan-Lamarre, P, 1286 Hoglund, E, 112 Hohenester, U, 698, 1478 Hojjatian, A, 836 Hojo, H, 252, 2308 Holburn, D, 2756 Holby, EF, 2976 Holguín-Momaca, J, 1748 Holler, M, 1026 Holm, E, 448 Holm, J, 1584, 1824 Holmestad, R, 1990, 3090 Holstad, TS, 1188 Holt, M, 364 Holtz, M, 184, 754, 2460 Holzapfel, B, 1056, 2876 Holzer, J, 1832 Home, FR, 2314 Homeniuk, D, 1052 Hong, Z, 348 Hoogenboom, J, 94, 558, 3234 Hooghan, K, 26 Hooshmand, MS, 3098 Hopkins, D, 1618, 2986 Hopkins, P, 112 Horak, J, 2026 Hörenz, C, 2250 Horgan, A, 2826 Hornbuckle, BC, 3046 Horner, AD, 3076 Horwath, J, 1210, 1312, 3426 Horák, M, 686 Hosemann, P, 1020, 1802, 2154, 3378 Hosogi, N, 1634 Hosoya, K, 1642 Hosseinkhannazer, H, 1642 Hossin, SS, 2284 Houard, J, 1260 House, R, 2724 House, S, 1308, 2242, 2868 Hovden, R, 896, 952, 1226, 1630, 2860 Howard, J, 2516 Howard, M, 3190 Howard, S, 1164 Howe, J, 112 Hoxley, D, 444, 2972 …”