title: Novel p53 target genes secreted by the liver are involved in non-cell-autonomous regulation.
abstract: The tumor-suppressor p53 is a transcription factor that prevents cancer development and is involved in regulation of various physiological processes. This is mediated both by induction of cell cycle arrest and apoptosis and by controlling the expression of a plethora of target genes, including secreted proteins. It has been demonstrated that p53 may exert its effect in non-cell-autonomous manner by modulating the expression of genes that encode for secreted factors. In this study, we utilized our microarray data to identify and characterize novel p53 target genes expressed in human liver cells and associated with steroid hormones processing and transfer. We identified the steroid hormones binding factors, sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG) and cytochrome P450 family 21 subfamily A polypeptide 2, as novel p53 target genes. Their expression and secretion was increased following p53 activation in various hepatic cells. We observed that p53 wild-type mice exhibited higher levels of CBG compared with their p53 null counterparts. We demonstrated that the induction of the steroid hormones binding factors can be mediated by binding to specific p53 responsive elements within their promoters. In addition, utilizing conditioned medium experiments we have shown that p53-dependent induction of SHBG secretion from liver cells enhances apoptosis of breast cancer cells. Moreover, depletion of SHBG abolished the induction of breast cancer cells death. The newly identified p53 target genes suggest a novel non-cell-autonomous tumor-suppressive regulation mediated by p53 that is central for maintaining organism homeostasis.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Charni
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Molchadsky
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Goldstein
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Solomon
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: P
authors.initials: P
authors.lastname: Tal
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Goldfinger
authors.affiliation: Department of Genetics, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Yang
authors.affiliation: The Flow Cytometry Unit, Life Sciences Faculty, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Z
authors.initials: Z
authors.lastname: Porat
authors.affiliation: Department of Genetics, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lozano
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: V
authors.initials: V
authors.lastname: Rotter
mesh_terms: D000818:Animals; D017209:Apoptosis; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism*; D061986:MCF-7 Cells; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012738:Sex Hormone-Binding Globulin / Q000235:genetics / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000235:genetics / Q000378:metabolism; D014156:Transcortin / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D012738:Sex Hormone-Binding Globulin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014156:Transcortin; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase