14-3-3 protein beta and zeta isoform (also known as tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta and zeta polypeptide) are encoded by the YWHAB gene and YWHAZ gene in humans. They have been linked to mitogenic signaling and the cell cycle machinery, and to cancer initiation and progression, respectively. The beta isoform has been shown to interact with RAF1 and CDC25 phosphatases and its overexpression is associated with invasion, migration, metastasis and proliferation of tumor cells and its elevated levels are correlated with tumor size, the number of lymph node metastases and a reduced survival rate. It is significantly overexpressed in lung cancer tissues, mutated chronic lymphocytic leukemia (M-CLL), gastric cancer tissues, aflatoxin B1-induced rat hepatocellular carcinoma K1 and K2 cells, as well as renal cell carcinoma cysts, and can potentially be used as a diagnostic and prognostic biomarker in the cancer. Numerous proteins involved in anti-apoptosis and tumor progression were also found to be differentially expressed in gastric cancer cells where 14-3-3 beta is overexpressed. 14-3-3 beta also interacts with human Dapper1 (hDpr1), a key negative regulator of Wnt signaling, via hDpr1 phosphorylation by protein kinase A, thus attenuating the ability of hDpr1 to promote Dishevelled (Dvl) degradation, and subsequently enhancing Wnt signaling. The zeta isoform is ubiquitously expressed and localized to most subcellular regions, including the cytoplasm, plasma membrane, mitochondria, and nucleus. Its overexpression and gene amplification in multiple cancers are correlated with poor prognosis and chemoresistance in cancer patients. 14-3-3 zeta has been identified as a biomarker with high sensitivity and specificity for diagnosis and prognosis in multiple tumor types, including hepatocellular carcinoma, head and neck cancer, indicating a potential clinical application for using 14-3-3 zeta in selecting treatment options and predicting cancer outcome. It also interacts with IRS1 protein, suggesting a role in regulating insulin sensitivity. 14-3-3 domains are an essential part of 14-3-3 proteins, a ubiquitous class of regulatory, phosphoserine/threonine-binding proteins found in all eukaryotic cells, including yeast, protozoa and mammalian cells.
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