RB Protein as a Cellular "Corral" for Growth-promoting Proteins
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Abstract:
The retinoblastoma (RB) susceptibility gene encodes a protein whose function prevents neoplastic transformation in a variety of cell types (for review, see Lee et al. 1988, 1990; Goodrich and Lee 1990). Loss or mutation of the gene elicits tumorigenesis in susceptible cells, and the reintroduction of the wild-type gene effects a reversion to a nontumorigenic state. Because the RB gene is expressed in all mammalian cell types examined so far, and because loss of a functional RB gene is associated with several cancers, the RB protein probably plays a general role in the regulation of cell growth.Keywords:
Reversion
Retinoblastoma protein
Retinoblastoma
Neoplastic transformation
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Mutational inactivation of the retinoblastoma gene (RB) is an invariant feature of the childhood eye cancer retinoblastoma and of tumor cells derived therefrom. In a previous study, retrovirus-mediated transfer of wild-type RB into cultured retinoblastoma cells resulted in a marked enlargement and reduced growth rate of these cells, as well as loss of their tumorigenic properties in nude mice. It was therefore difficult to separate the proposed growth-suppressing and tumor-suppressing activities of RB protein. Here, we show that clones of RB-reconstituted retinoblastoma cells can be isolated that stably express apparently normal RB protein for at least 20 months of continuous culture. These clones were indistinguishable from nonreconstituted cells by multiple parameters including morphology, growth rate, and cell cycle distribution. Despite similar phenotypes in culture, clones with stable RB expression were uniformly nontumorigenic in nude mice, whereas those that lost such expression regained their tumorigenic properties. These results indicate that the tumorigenicity of these cells is entirely determined by the presence or absence of exogenous RB protein expression and that suppression of tumorigenicity is distinct from inhibition of cellular growth in culture.
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Human papillomavirus type 16 E7 is considered to be a major viral oncoprotein playing an important role(s) in cervical cancers. E7 protein was shown to bind to the protein product of the retinoblastoma gene (RB), while simian virus 40 large T and adenovirus E1A were also shown to possess binding activity to RB protein. The RB protein is a cell cycle regulator that is highly phosphorylated specifically in S, G2, and M, whereas it is underphosphorylated in G0 and G1. Recently, large T was demonstrated to bind preferentially to the underphosphorylated RB protein, which is considered to be an active form restricting cell proliferation. However, it is not known whether E7 can bind to phosphorylated RB protein. We successfully purified large quantities of unfused human papillomavirus type 16 E7 protein expressed in Escherichia coli by using a T7 promoter-T7 RNA polymerase system. The purified E7 protein was demonstrated to bind preferentially to the underphosphorylated RB protein.
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Mutation, absence or abnormal functioning of retinoblastoma protein are fundamental elements of uncontrolled growth in human cancer. In this study, we analyze the expression of retinoblastoma protein and phosphorylated retinoblastoma protein in melanocytic tumors in vivo. Real-time RT-PCR and immunohistochemistry (tissue microarrays and conventional histological sections) reveal that retinoblastoma protein is progressively upregulated in advanced and metastatic malignant melanomas in vivo. However, this increase is paralleled by increased retinoblastoma protein inactivation due to protein phosphorylation. Interestingly, retinoblastoma protein phosphorylation occurs not homogeneously, but with a 'growth zone'-related pattern. In superficial spreading melanomas a subepidermal-lateral maximum of phosphorylated retinoblastoma protein can be frequently observed. Accordingly, nodular vertically invasive melanomas are characterized by a strong staining of phosphorylated retinoblastoma protein in deep-dermal invading protrusions of the tumor. Furthermore, Kaplan-Meier analysis of 13 cases of advanced melanomas with long-time follow-up suggests a significant negative impact of retinoblastoma protein phosphorylation on survival of melanoma patients independent of tumor thickness. We conclude that the evaluation of phosphorylated retinoblastoma protein in melanocytic tumors could become a helpful adjunct in clinicopathological routine.
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Abstract The underlying cause of human retinoblastoma is complete inactivation of both copies of the RB1 gene. Other chromosome abnormalities, with the most common being extra copies of chromosome arm 6p, are also observed in retinoblastoma. The RB protein has previously been shown to interact with TFAP2 transcription factors. Here, we show that TFAP2A and TFAP2B , which map to chromosome arm 6p, are expressed in the amacrine and horizontal cells of human retina. TFAP2A RNA can readily be detected in retinoblastoma cell lines and tumors; however, the great majority of retinoblastoma cell lines and tumors are completely devoid of TFAP2A protein and TFAP2B RNA/protein. Transfection of TFAP2A and TFAP2B expression constructs into retinoblastoma cells induces apoptosis and inhibits proliferation. Our results suggest that a consequence of loss of RB1 gene function in retinoblastoma cells is inactivation of TFAP2A and TFAP2B function. We propose that inability to differentiate along the amacrine/horizontal cell lineages may underlie retinoblastoma tumor formation. © 2010 Wiley‐Liss, Inc.
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Abstract The sections in this article are Introduction Retinoblastoma Proteins and the Tumor Suppressor Concept The Retinoblastoma Pathway is Conserved in Animals and Plants Retinoblastoma Proteins form Complexes with E2F Transcription Factors to Control Entry into the Cell Cycle G1 Restriction Point Control is Mediated by Retinoblastoma Protein Phosphorylation Animal and Plant DNA Viruses Target Retinoblastoma Proteins to Induce Host DNA Replication Information on Retinoblastoma Protein Function in Animal Development is Still Incomplete Retinoblastoma Proteins may have Conserved Functions in Germline Development Retinoblastoma Proteins Connect Stem Cell Maintenance to Cell Proliferation and Differentiation Perturbation of RBR during Leaf Development Affects Cell Proliferation and Control of DNA Replication Roles of Retinoblastoma Proteins in Transcription Activation and Repression Retinoblastoma Proteins Interact with Polycomb Group Complexes in Controlling Gene Expression Conclusion Acknowledgments
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Retinoblastoma, a rare pediatric eye tumor, has served as an important model for the heritable predisposition to cancer. The retinoblastoma protein, Rb , functions as a tumor suppressor by controlling progression through the cell cycle. Rb function is regulated primarily by its phosphorylation state, which is determined by the complex interaction of multiple kinases and their inhibitors that together form the ‘Rb pathway’. This pathway has been found to be functionally inactivated in almost all types of cancer. Despite recent advances in our understanding of Rb function, the precise role of Rb loss in the development of retinoblastoma remains unclear. Recent work in genetically altered mice has suggested that an additional mutation in another gene is required for retinal tumor formation. An alternative model presented here is based on the noncell-autonomous functions of Rb contributing to tumorigenesis.
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The RB gene was discovered 20 years ago because of its role in the childhood eye cancer retinoblastoma. However, surprisingly little progress was made in defining the role of RB protein in the retina. In the last two years, new models exploiting conditional deletion of the mouse Rb gene have altered this picture radically. These models provide insight into the first Rb function, the cell of origin of retinoblastoma, the window during which Rb acts, distinct cell-specific defenses against Rb loss, the number and type of post-Rb lesions required for transformation, why pediatric tumors exist, the controversial role of the p53 pathway in retinoblastoma, and the reason why the disease is virtually unique to humans. Two years have dramatically improved our understanding of Rb function in the tissue that gave us this important tumor suppressor.
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