Regulation of cyclin D1 expression by PKC signaling in intestinal epithelial cells
Başlık çevirisi mevcut değil.
- Tez No: 402954
- Danışmanlar: DR. JENNIFER BLACK
- Tez Türü: Doktora
- Konular: Mikrobiyoloji, Moleküler Tıp, Microbiology, Molecular Medicine
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2005
- Dil: İngilizce
- Üniversite: State University of New York at Buffalo
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 280
Özet
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Özet (Çeviri)
Members of the protein kinase C (PKC) family of serine/theronine kinases are recognized as major players in cell cycle regulation in numerous systems. Previous studies in this laboratory have demonstrated that PKC signaling, and PKCα in particular, negatively regulates cell cycle progression in intestinal epithelial cells. Activation of the phorbol ester responsive PKC isozymes, PKCα, PKCδ, and PKCε, or of PKCα alone, in IEC-18 nontransformed intestinal crypt cells induces hallmark molecular events of G0 exit, including downregulation of cyclin D1. Conversely, depletion of PKCα, δ and ε is associated with hyperinduction of cyclin D1 protein in these cells. Cyclin D1 is limiting for cell cycle progression in intestinal epithelial cells and plays a critical role in tumor progression; thus, understanding of its regulation by PKC signaling, which is markedly reduced in intestinal tumors, is of key importance. Elucidation of the molecular pathways underlying the bimodal regulation of cyclin D1 expression determined by the activation status of PKC isozyme(s) was the focus of the current study. In the first part of this work, we (a) characterized the pathways involved in PKC agonist-induced downregulation of cyclin D1 and (b) determined the specific PKC isozyme involved. The data point to PKCα as a major regulator of cyclin D1 translation. PKC/PKCα activation does not alter cyclin D1 transcription, mRNA stability, or mRNA transport to reduce cyclin D1 protein levels. Furthermore, pulse-chase analysis and exogenous expression of cyclin D1 proteolysis mutants excluded a role for changes in cyclin D1 protein stability. Instead, PKC/PKCα activity was shown to inhibit cyclin D1 synthesis, in association with blockade of key regulators of both translation initiation and elongation. Upon PKC/PKCα activation, the function of eukaryotic initiation factor 4E (eIF4E) was rapidly blocked via activation of its inhibitory binding factor, eIF4E binding protein 1 (4E-BP1), indicating PKC-induced shut-down of cap-dependent translation initiation. Furthermore, PKC/PKCα activation promoted rapid inhibition of eukaryotic elongation factor 2 (eEF2), a key regulator of the elongation step of translation, via increased phosphorylation of Thr56. These negative modulatory effects of PKC/PKCα signaling on regulators of translation initiation and elongation were reversed coincident with downregulation of PKC isozymes, paralleling the recovery of cyclin D1 levels and re-entry of cells into the cell cycle. Interestingly, continued absence of PKC signaling resulted in aberrant hyperinduction of cyclin D1 protein and increased proliferation of IEC-18 cells. Understanding of this effect and its implications for intestinal tumor development was the focus of the second phase of this study. Levels of cyclin D1 in PKC-depleted cells were found to be comparable with those seen in neoplastic intestinal cells, offering a perspective on the frequent reduction/absence of PKC/PKCα signaling in intestinal malignancies. Findings from biosynthetic labeling experiments revealed enhanced synthesis of cyclin D1 in PKC-depleted cells, in the absence of changes in cyclin D1 message levels, suggesting the involvement of post-transcriptional mechanisms. Several lines of evidence obtained in the current study point to a role of PKCα signaling, in particular, in repressive control of cyclin D1 accumulation. First, selective inhibition of PKCα activity was found not only to block PKC agonist-induced downregulation of cyclin D1, but also to markedly elevate cyclin D1 steady state levels in cycling cells. Second, targeted silencing of PKCα mRNA, but not of PKCδ or PKCε mRNA, resulted in aberrant elevation of cyclin D1 protein in IEC-18 cells. Third, abrogated PKCα expression in association with aberrantly high levels of cyclin D1 was detected in colonic adenocarcinoma cell lines derived from human tumors and Apcmin mouse adenomas. Based on these findings, PKCα signaling is proposed to be a key regulator of cyclin D1 expression in intestinal epithelial cells. Reduced PKCα signaling may provide a proliferative advantage to intestinal cells through relief of its preventive role on cyclin D1 accumulation, and thus contribute to malignant transformation. This study also highlights the potential importance of translational control in maintenance of intestinal epithelial homeostasis.
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