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Fig. 2 | Nutrition & Metabolism

Fig. 2

From: Milk disrupts p53 and DNMT1, the guardians of the genome: implications for acne vulgaris and prostate cancer

Fig. 2

Working model illustrating the potential impact of milk exosome-derived miRNAs on the expression of p53. a. In the absence of milk miRNAs, p53 is abundantly expressed. p53 inhibits mechanistic target of rapamycin complex 1 (mTORC1) signaling and directly reduces the expression of IGF-1 receptor (IGF1R). p53 enhances sestrin1/2-mediated activation of AMK kinase (AMPK), a critical negative regulator of mTORC1. Furthermore, p53 induces the expression of FOXO1, which is a negative regulator of androgen receptor (AR). The expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is upregulated by p53, which activates the extrinsic and intrinsic (mitochondrial) pathway of apoptosis. AR expression is negatively regulated by p53 resulting in decreased AR-mediated expression of miRNA-125b, which targets the pro-apoptotic proteins Bak and p53 at the mitochondrial membrane. This stimulates the interaction of p53 with Bak promoting the intrinsic pathway of apoptosis. b. During milk intake, milk exosomal miRNAs interrupt p53 signaling. This promotes the PI3K-AKT-mTORC1 pathway enhancing the expression of survivin, which is a negative regulator of caspase 3. Furthermore, milk miRNAs via attenuation of p53 and FOXO1 expression enhance AR signaling with subsequent upregulation of miRNA-125b. Increased miRNA-125b expression via AR signaling and milk miRNA-125b uptake down-regulate Bak-p53-interaction suppressing the intrinsic pathway of apoptosis. Thus, milk orchestrates both pro-survival and anti-apoptotic signaling, a most favorable constellation for the growing infant but a disastrous promoter of diseases in patients associated with disrupted p53 homeostasis such as acne vulgaris and prostate cancer

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