Prostate cancer is characterized by epigenetic silencing of 14-3-3σ expression

The crystal structure of the non-liganded 14-3-3σ protein: insights into determinants of isoform specific ligand binding and dimerization

“…14-3-3σ expression is lost in numerous carcinomas either due to epigenetic silencing by CpGmethylation, which has been detected in a large number of different tumor types [1,2], or due to mutation of p53, which directly induces expression of 14-3-3σ [4]. Epigenetic silencing of 14-3-3σ has been detected at a high frequency in carcinomas of the breast [5], ovary [6], endometrium [6], prostate [7], skin [8], lung [9] and liver [10]. After DNA-damage, p53-induced 14-3-3σ expression mediates a cell cycle arrest in the G 2 -phase [4], presumably by cytoplasmic sequestration of CDC2/cyclin B1 complexes [11].…”

“…After DNA-damage, p53-induced 14-3-3σ expression mediates a cell cycle arrest in the G 2 -phase [4], presumably by cytoplasmic sequestration of CDC2/cyclin B1 complexes [11]. Experimental removal of the 14-3-3σ gene prevents a stable G 2 /M-arrest after DNA-damage and sensitizes cells to DNA-damaging treatments commonly used in cancer therapy [7,11].…”

Targeted Proteomic Analysis of 14-3-3ς, a p53 Effector Commonly Silenced in Cancer

“…After DNA damage, p53-induced expression of 14-3-3 mediates a cell cycle arrest in the G 2 phase (2) presumably by cytoplasmic sequestration of CDC2-cyclin B1 complexes (9). Experimental removal of the 14-3-3 gene prevents a stable G 2 /M arrest after DNA damage and sensitizes cells to DNA-damaging treatments commonly used in cancer therapy (5,9). 14-3-3 proteins form dimers that bind to protein ligands following serine/ threonine phosphorylation by basophilic kinases, such as cAMP-dependent protein kinase or protein kinase B/AKT, of two canonical 14-3-3-binding motifs, which have been identified as R(S/X)XpSXP and RXXXpSXP where pS represents phosphoserine or phosphothreonine and X represents any amino acid (10).…”

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

“…This included, for example, the calcium binding proteins S100A2 and A14 55 , the 14-3-3 protein stratifin 56, 57 , laminin A 58 , claudin 7 59 , prostasin 60 , P cadherin 61 , and kallikrein 5 62 . Cyclin D2 is considered an activator of cell cycle progression but was induced by NKX3.1.…”

“…Although p53 was upregulated neither at the mRNA nor protein level ( Figure 6C), a finding which is consistent with the well-established activation of p53 at the post-translational level, the network indicated robust induction of some of its known target genes. As shown in Figure 5B, this included the 14-3-3 sigma protein stratifin (SFN), an epithelial differentiation marker missing from many prostate cancers 56, 72 , the cyclin-dependent kinase inhibitor p21 (CDKN1A, 73 ), and the p53 apoptosis effecter PERP 74 . Induction of p21 protein by NKX3.1 was confirmed by immunoblotting ( Figure 6C).…”