Novel p53 target genes secreted by the liver are involved in non-cell-autonomous regulation

Area of Science:

• Molecular Biology
• Oncology
• Endocrinology

Background:

• The tumor suppressor p53 is a key regulator of cellular processes, including cell cycle arrest and apoptosis.
• p53 influences gene expression, including genes encoding secreted proteins, suggesting non-cell-autonomous functions.
• Understanding p53's role in regulating secreted factors is crucial for cancer prevention and homeostasis.

Purpose of the Study:

• To identify and characterize novel p53 target genes involved in steroid hormone processing and transfer in human liver cells.
• To investigate the non-cell-autonomous tumor-suppressive functions of p53 through secreted factors.

Main Methods:

• Microarray analysis of human liver cells to identify p53 target genes.
• Quantitative analysis of gene expression and protein secretion (SHBG, CBG) following p53 activation.
• In vivo studies using p53 wild-type and null mice.
• Reporter assays to confirm p53 binding to gene promoters.
• Conditioned medium experiments with breast cancer cells to assess apoptosis induction.

Main Results:

• Identified sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), and CYP21A2 as novel p53 target genes.
• p53 activation increased the expression and secretion of SHBG and CBG in hepatic cells.
• p53 wild-type mice showed higher CBG levels than p53 null mice.
• p53 directly binds to responsive elements in the promoters of these genes.
• p53-induced SHBG secretion enhanced breast cancer cell apoptosis, which was abolished by SHBG depletion.

Conclusions:

• p53 regulates key steroid hormone binding proteins, suggesting a role in steroid hormone homeostasis.
• p53 exerts non-cell-autonomous tumor suppression by inducing SHBG secretion, leading to breast cancer cell death.
• These findings reveal a novel mechanism of p53-mediated tumor suppression crucial for organismal homeostasis.