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Home | The Scope | What's New | Grand Rounds | Research In Progress RESEARCH IN PROGRESS PRESENTATION "Investigating the role of 14-3-3 sigma in an in vitro Prostate Cancer Model" November 28, 2005
14-3-3 proteins are a family of highly conserved acidic dimeric proteins that participate in the regulation of a wide variety of cellular functions, such as cell proliferation, apoptosis, and maintenance of genomic integrity (Mhawech, 2005). Seven isoforms of 14-3-3 are expressed in humans, and their effects are diverse and dependent on factors such as subcellular localization and cellular subtype (Fu, et al., 2000). Ware and colleagues have recently identified a particular isoform, 14-3-3s (also called human mammary epithelium-specific marker 1 (HME-1) or stratifin), as a putative phosphorylation target in M12 AR (+) cells when stimulated by either DHT or EGF (Huang, et al., 2004). In addition, immunocytochemical analysis of M12 AR(+) cells after stimulation with DHT or EGF displayed an altered staining distribution of 14-3-3s , showing greater reactivity in the nucleus. A similar pattern of increased nuclear localization was also noted to correlate with prostate tumors with higher grade Gleason scores, in comparison to benign prostate glands. This translocation of 14-3-3 s to the nucleus in response to signaling peptides is consistent with what is known about the shuttling function of 14-3-3 proteins, which can provide a mechanism of sequestering bound proteins into distinct subcellular compartments. Proteomic analysis supports the hypothesis that 14-3-3 s acts as a common member of both the AR and EGF signaling pathways, indicating 14-3-3s as a key mediator of androgen-independent prostate cancer growth. Despite an accumulating body of research, the role of 14-3-3 proteins in the development of prostate and other cancers remains obscure. 14-3-3s is ubiquitously expressed at high levels in normal prostate epithelium, and its expression is decreased in prostatic intraepithelial neoplasia (PIN) and further decreased in prostate adenocarcinoma. 14-3-3 s expression has been shown to be reduced in a wide variety of carcinomas, including breast (Ferguson, et al., 2000), prostate (Cheng, et al., 2004; Urano, et al., 2004), bladder (Moreira, et al., 2004), skin (Lodygin et al., 2003), and various hematological malignancies (Lodykin and Hermeking, 2005). This 14-3-3s downregulation has been attributed to a variety of mechanisms: epigenetic silencing by CpG methylation, mutation or other dysregulation of p53, which directly induces 14-3-3 s (Hermeking, et al., 1997), and in breast epithelial cells, interaction with an E3 ubiquitin ligase estrogen-induced zinc finger protein (EFP), resulting in ubiquitinylation and rapid degradation of 14-3-3 s (Urano, et al., 2002). The consequences of possessing altered levels of 14-3-3s are isoform specific, and have yet to be clearly elucidated. Additional study of 14-3-3s function within a prostate cancer model possessing a consistent genetic lineage could allow for additional insight into the malignant progression of prostate cancer cells, and in particular, contribute to knowledge about the signaling pathways involved in the transition from androgen-dependent to androgen-independent growth. For a printable version of this Research in Progress presentation, click here. For more information visit the Functional Genomics Laboratory web page. For more information about VCU Pathology
Research in Progress presentations contact Updated December 14, 2005 |
This week's Research in Progress presentation, given by Amy Hawkins, in the