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The 14-3-3 proteins: gene, gene expression, and function.

Yasuo Takahashi
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Abstract

14-3-3 proteins were discovered by Moore and Perez in the soluble extract of bovine brain. These proteins are highly abundant in the brain. In this review 14-3-3 cDNA cloning, nucleotide sequence of 14-3-3 cDNA, the structure of 14-3-3 gene and 14-3-3 gene expression, in situ hybridization of 14-3-3 mRNA in the brain, the function and regulation of 14-3-3 protein, the binding of 14-3-3 protein to other proteins, the effects of 14-3-3 protein on the binding of a protein to other proteins, and the effect on protein kinase, etc., are concisely described. From the recent rapid development of proteom technology, markedly more target proteins of 14-3-3 protein should be discovered.

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14-3-3 ProteinsAmino Acid SequenceAnimalsBase SequenceDNA, ComplementaryGene ExpressionIn Situ HybridizationMiceMolecular Sequence DataPhosphorylationProtein BindingRNA, MessengerTyrosine 3-MonooxygenaseJournal ArticleReview

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Yasuo Takahashi. 2003. The 14-3-3 proteins: gene, gene expression, and function.. https://doi.org/10.1023/a%3A1024296932670

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Mathematical modeling suggests 14-3-3 proteins modulate RAF paradoxical activation.

RAF inhibitor "paradoxical activation" (PA) is a phenomenon where RAF kinase inhibitors increase RAF kinase signaling. Through mathematical modeling and experimental data analysis, we recently demonstrated that the combination of conformational autoinhibition (CA) with the disruption of CA by RAF inhibitors plays an important role in PA. 14-3-3 proteins are known to modulate RAF CA and RAF dimerization. We here extend our mathematical model to include both roles of 14-3-3 proteins, and we derive rigorous analytical expressions of RAF signal regulation as modulated by 14-3-3 proteins. We then use the model to investigate how 14-3-3 proteins may modulate PA. We mathematically show 14-3-3 protein stabilization of the autoinhibited form of RAF should potentiate PA, while 14-3-3 protein stabilization of the active RAF dimer should reduce PA. Our analysis suggests that the net-effect will often be a potentiation of PA, and that 14-3-3 proteins may be capable of inducing PA for RAF inhibitors that normally show little to no PA. We test model-based insights experimentally with two different approaches: forced increases in 14-3-3 expression (which we find amplifies PA) and evolved resistance assays (which suggest increased 14-3-3 expression may contribute to resistance to RAF inhibitors). Overall, this work supports a role for 14-3-3 in modulating RAF-inhibitor mediated paradoxical activation.

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PubMed2007

Promoter hypermethylation of GSTP1, AR, and 14-3-3sigma in serum of prostate cancer patients and its clinical relevance.

OBJECTIVE: Hypermethylation of tumor suppressor genes (TSG) is thought to play an important role in tumorigenesis of prostate cancer. The main focus of research was the detection of TSG hypermethylation in cancer tissue. Our aim was to evaluate the feasibility of detection of hypermethylated genes in serum of prostate cancer patients and its correlation with clinicopathological parameters. METHODS: One hundred twenty-five serum samples from 62 patients with hormone refractory prostate cancer (HRPC), 14 patients with early disease, and 49 healthy controls were examined. After DNA extraction and sodium-bisulfite treatment, conventional methylation-specific PCR (MSP) was performed for glutathione S-transferase P1 (GSTP1), androgen receptor (AR), and 14-3-3sigma. RESULTS: In serum of HRCP patients, frequency of GSTP1, AR, and 14-3-3sigma hypermethylation was 32.2, 40.3, and 86.6%, respectively. In serum of patients with early disease frequency of GSTP1, AR, and 14-3-3sigma, hypermethylation was 21.4, 35.7, and 85.7%. In healthy controls, frequency of GSTP1, AR, and 14-3-3sigma hypermethylation was 0, 26.5, and 55.1%, respectively. There was a significant increase of frequency of TSG hypermethylation for GSTP1 and 14-3-3sigma in HRPC patients, in comparison with healthy controls. GSTP1 hypermethylation in HRPC patients was significantly correlated with differentiation of cancer and metastatic disease. CONCLUSIONS: Hypermethylation of TSG can be detected in serum of prostate cancer patients. Some hypermethylated TSG can be detected in serum of healthy controls. GSTP1 was not detectable in controls and correlated significantly with Gleason score and stage of disease. Therefore, this gene may be a promising new tool in prostate cancer diagnosis.

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PubMed2007

DYRK1A autophosphorylation on serine residue 520 modulates its kinase activity via 14-3-3 binding.

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