p53 attenuates AKT signaling by modulating membrane phospholipid composition

Abstract

The p53 tumor suppressor is the central component of a complex network of signaling pathways that protect organisms against the propagation of cells carrying oncogenic mutations. Here we report a previously unrecognized role of p53 in membrane phospholipids composition. By repressing the expression of stearoyl-CoA desaturase 1, SCD, the enzyme that converts saturated to mono-unsaturated fatty acids, p53 causes a shift in the content of phospholipids with mono-unsaturated acyl chains towards more saturated phospholipid species, particularly of the phosphatidylinositol headgroup class. This shift affects levels of phosphatidylinositol phosphates, attenuates the oncogenic AKT pathway, and contributes to the p53-mediated control of cell survival. These findings expand the p53 network to phospholipid metabolism and uncover a new molecular pathway connecting p53 to AKT signaling.

Sustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy

“…Previous work has shown that SREBP-1 is activated through several mechanisms including, regulation by the PTEN/PI3K/Akt/mTOR pathway 20 , 44 , p53 19 , 45 , modulation of MAPK signaling by KRAS 46 and by direct SREBP phosphorylation by Erk1/2 47 , 48 . Our work identifies mutant BRAF as another key modulator of SREBP-1 processing and function.…”

Phospholipid profiling identifies acyl chain elongation as a ubiquitous trait and potential target for the treatment of lung squamous cell carcinoma

“…MYC is often amplified in lung SCC [ 20 , 21 ] and we found evidence from the UCSC genome browser that ELOVL6 expression is controlled by MYC ( Supplementary Figure S6 ). TP53, which is often mutated in lung cancer [ 22 ], was recently shown to repress the transcription factor SREBP1c and accordingly several ELOVLs [ 29 ]. Besides changes in the expression of ELOVLs, an increase in substrate availability could drive the elongation process in tumors.…”

Phosphatidylinositol synthesis at the endoplasmic reticulum

“…In a separate study, the role of wild type p53 was examined in HCT116 cell line [71]. (This cell line was also used in the previous study and had a predominance of C36 and C34 carbons in their PI lipids [11]).…”

“…18:1/18:1) to either saturated or mono-unsaturated. These changes were most prominent in the PI species[71]. The increase in p53 resulted in a decrease in both PI(4,5)P2 and PI(3,4,5)P3.…”