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Oncogenes and cell proliferation
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Oncogenes and cell proliferation Editorial overview Fred Cross* and Jim Roberts† Addresses *Box 237, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA; e-mail: [email protected] † Division of Basic Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., mailstop A3-023, PO Box 19024, Seattle, Washington 98109-1024, USA; e-mail: [email protected] Current Opinion in Genetics & Development 2001, 11:11–12 0959-437X/01/$ — see front matter © 2001 Elsevier Science Lid. All rights reserved. Abbreviations MCM minichromosome maintenance Rb retinoblastoma protein
The control of cell proliferation has an impact on both basic and practical problems in biology. Many of these problems intersect in the study of cancer biology, which is one organizing focus of this issue of Current Opinion in Genetics & Development. A great deal of progress in studying the basic cell cycle has revealed a central and highly conserved cell-cycle ‘engine’ powered by cycles of protein phosphorylation and dephosphorylation, and interlocking cycles of transcription, protein synthesis and degradation. This cell-cycle engine is engaged inappropriately in cancer cells. It remains unclear to what extent the genetic deregulations inducing cancer directly modulate components of the cell cycle engine, as distinct from sending a generalized inappropriate ‘enter the division cycle’ signal to an otherwise unchanged engine. One generalized signal that could be proposed is simply a higher rate of cell growth and protein synthesis. Early work in yeast showed that cell growth is limiting for cell cycle progression; thus all else being equal, faster growth will trigger more cell cycles. This would be an appealingly simple model for inducing inappropriate cell proliferation in tumors. The questions of coordination of growth and division, the roles of oncogenes in driving cell growth, and how cell growth is inter-regulated with cell-cycle control components such as cyclins, are central issues in understanding oncogenesis as well as normal cell-cycle progression. The observation that eIF4E, an initiation factor in protein synthesis, acts as an oncogene in some assays clearly supports the idea that growth rates and protein synthesis in particular can be primary in driving cell proliferation. This could be caused by either general or targeted increases in cyclin expression; increases in cyclin expression could then conversely regulate cell growth pathways. This complex set of issues is well covered in reviews by Pyronnet and Sonenberg (pp 13–18) on regulated translation and its relevance to cell-cycle machinery, and by Prober and Edgar
(pp 19–26) on the inter-relationships between oncogene function, growth rate, and cyclin expression. Retinoblastoma protein (Rb) function also feeds into the loop because cyclin D — which may be activated by growth, and also may activate growth — inhibits it, resulting in expression of many genes including cyclin E. Intriguingly, even though the early yeast literature supported a simple relationship between growth and division, Pyronnet and Sonenberg review evidence for specific interaction between protein synthesis and translation of G1 cyclins in yeast, especially Cln3. There remains no evidence in yeast for regulation in the reverse direction, in which cell-cycle control machinery also regulates growth. Prober and Edgar review the evidence for this in Drosophila. It should be pointed out that this kind of control has not been exhaustively sought in yeast, although the literature does suggest that rather high rates of cell growth in yeast can persist in the absence of a functioning cell cycle. Perhaps the most basic aspect of cell growth is the generation of ATP from oxidation of carbohydrates; a critical requirement for tumors is thus oxygen. Different aspects of this problem are discussed in two reviews. Ivan and Kaelin (pp 27–34) review work on the Von Hippel–Lindau tumor suppressor, which may help block tumor formation by assembling multiprotein complexes that catalyze the ubiquitination and degradation of an oxygen-regulated transcription factor. Higher levels of this factor can lead to expression of angiogenesis-inducing genes. Giordano and Johnson (pp 35–40) review tumor angiogenesis in general. There are many aspects to the interaction of tumor cells with their environment in addition to achieving an adequate oxygen supply. The cancer cell interacts with its microenvironment by cytoskeletal changes leading to altered integrin–extracellular-matrix interactions. The cytoskeleton is also coregulated with complex intracellular signal-transduction pathways affecting many aspects of cell growth and gene expression. These issues are discussed in reviews by Pawlak and Helfman (pp 41–47), and Assoian and Schwartz (pp 48–53). Beyond interactions with extracellular components, tumor cells must interact with neighboring normal cells. This is an extremely complex, underexplored and underappreciated aspect of tumor biology. There is considerable evidence, reviewed by Tlsty and Hein (pp 54–59), that reciprocal interactions between tumor cells and the surrounding stromal cells makes critical contributions to the evolution of the tumor phenotype. This group of reviews suggests that a more complete understanding of tumor biology will require that we view the tumor not as a collection of autonomous, rogue cells
12
Oncogenes and cell proliferation
but rather as an organ composed of interdependent parts — tumor cells, blood vessels and stroma. This view of tumor biology justifies the application of more global approaches toward identifying changes in gene expression that contribute to the tumor phenotype. Rather than trying to understand tumorigenesis ‘one gene at a time’ it is clear that we now need to explore the idea of characterizing tumor progression in terms of large-scale changes in gene expression. This approach is reviewed by Porter (pp 60–63), who describes recent progress in the application of DNA microarrays to the analysis of human tumors. There is considerable evidence now that in addition to modulating cell growth rates, oncogenic mutations may also impinge directly on cell-cycle machinery. The gene for SV40 T antigen is one of the earliest described genetic inducers of cancer. Along with its abilities to interfere with cell regulatory machinery such as the Rb pathway, T antigen also participates directly in SV40 DNA replication, serving as the origin-binding protein as well as a replicative helicase. It is plausible that this serves the virus well by removing potential cellular controls on replication. At least in yeast, it is clear that the origin-binding aspect of T antigen is provided for cellular origins by the origin recognition complex, perhaps in combination with Cdc6. The cellular replicative helicase equivalent to T antigen has been harder to pin down. The review by Labib and Diffley (pp 64–70) focuses on the question of whether the MCM (minichromosome maintenance) complex is a good candidate for this helicase. Although some evidence supports this idea, the case is not closed, and Labib and Diffley (pp 64–70) ultimately raise the question of whether an exact equivalent to the T antigen function exists for cellular DNA replication. To date, aside from the SV40 example, there is no evidence for oncogenic stimuli directly targeting or co-opting DNA replication machinery, and thus DNA replication may be an example of a part of the cell-cycle machinery that is only indirectly activated by oncogenesis. New insights into regulation of the chromosomal helicase, be it the MCM complex or something else, should help to resolve this important question. A key aspect to keeping cell cycles orderly is constituted by the surveillance mechanisms or checkpoints that probably function to prevent aneuploidy and other errors in division. These checkpoints are important in regulating cancer because such errors in division are probably central to generating mutations that can affect cell growth and cell-cycle control. There are two main branches of checkpoint control: one monitoring spindle function, and one monitoring DNA damage. Much work has implicated derangements of both checkpoints in oncogenesis. The
involvement of ATM-related protein kinases in the DNA damage checkpoint is reviewed in mammalian systems by Shiloh (pp 71–77), and the regulation by these kinases and others of the Chk1–Cds1–Cdc25 system in yeast — many but not all aspects of which appear to be conserved in mammalian cells — is reviewed by Walworth (pp 78–82). Wassman and Benezra (pp 83–90) review the spindle checkpoint from basic biology to cancer. Lastly we turn to the question of how tumor cells override the normal physiological limitations on cell division. These limitations are imposed by two general processes. First is the limitation imposed by programs of cellular differentiation, and second is the ultimate restriction facing cell division — the universal program of cellular senescence. Thus, tumorigenesis does not only involve the inappropriate expression of extrinsic and intrinsic signals that promote cell growth and proliferation. It is also accompanied by mechanisms that override cellular programs for terminal phenotypic differentiation, and by cellular changes that permit clonal expansion beyond the cell’s normally limited lifespan. Zhu and Skoultchi (pp 91–97) discuss the fact that functional differentiation almost always involves the cessation of cell division and, in this context, review evidence that cell-cycle regulatory proteins may themselves regulate cellular differentiation. Changes in certain cell-cycle regulators can allow differentiated cells to proliferate well beyond their normal capacity to do so, and this may have important implications for the origin of tumor cells. Wright and Shay (pp 98–103) review evidence that telomere attrition is the mechanism underlying cellular senescence and evidence that activation of telomerase is sufficient, on its own, for cells to overcome the senescence-induced blockade to proliferation. They suggest that the counter-examples of human epithelial cells and murine fibroblasts, which undergo senescence in vitro despite expression of active telomerase, are not exceptions to this general principle but rather represent artifacts of cell culture. It is obviously of essential practical concern to use the information generated by our studies of tumor biology to learn how better to eradicate the disease in patients. Huang and Oliff (pp 104–110) describe one important approach toward the development of new targeted attacks on tumor cells by incorporating the particular genetic and molecular features of cancer cells into the design of specialized anti-tumor drugs. This review is intended to stimulate the research community into thinking about how the progress being made in understanding tumor biology could be applied in a rational way to the design of better therapeutic agents.
Oncogenes and cell proliferation Editorial overview Fred Cross* and Jim Roberts† Addresses *Box 237, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA; e-mail: [email protected] † Division of Basic Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., mailstop A3-023, PO Box 19024, Seattle, Washington 98109-1024, USA; e-mail: [email protected] Current Opinion in Genetics & Development 2001, 11:11–12 0959-437X/01/$ — see front matter © 2001 Elsevier Science Lid. All rights reserved. Abbreviations MCM minichromosome maintenance Rb retinoblastoma protein
The control of cell proliferation has an impact on both basic and practical problems in biology. Many of these problems intersect in the study of cancer biology, which is one organizing focus of this issue of Current Opinion in Genetics & Development. A great deal of progress in studying the basic cell cycle has revealed a central and highly conserved cell-cycle ‘engine’ powered by cycles of protein phosphorylation and dephosphorylation, and interlocking cycles of transcription, protein synthesis and degradation. This cell-cycle engine is engaged inappropriately in cancer cells. It remains unclear to what extent the genetic deregulations inducing cancer directly modulate components of the cell cycle engine, as distinct from sending a generalized inappropriate ‘enter the division cycle’ signal to an otherwise unchanged engine. One generalized signal that could be proposed is simply a higher rate of cell growth and protein synthesis. Early work in yeast showed that cell growth is limiting for cell cycle progression; thus all else being equal, faster growth will trigger more cell cycles. This would be an appealingly simple model for inducing inappropriate cell proliferation in tumors. The questions of coordination of growth and division, the roles of oncogenes in driving cell growth, and how cell growth is inter-regulated with cell-cycle control components such as cyclins, are central issues in understanding oncogenesis as well as normal cell-cycle progression. The observation that eIF4E, an initiation factor in protein synthesis, acts as an oncogene in some assays clearly supports the idea that growth rates and protein synthesis in particular can be primary in driving cell proliferation. This could be caused by either general or targeted increases in cyclin expression; increases in cyclin expression could then conversely regulate cell growth pathways. This complex set of issues is well covered in reviews by Pyronnet and Sonenberg (pp 13–18) on regulated translation and its relevance to cell-cycle machinery, and by Prober and Edgar
(pp 19–26) on the inter-relationships between oncogene function, growth rate, and cyclin expression. Retinoblastoma protein (Rb) function also feeds into the loop because cyclin D — which may be activated by growth, and also may activate growth — inhibits it, resulting in expression of many genes including cyclin E. Intriguingly, even though the early yeast literature supported a simple relationship between growth and division, Pyronnet and Sonenberg review evidence for specific interaction between protein synthesis and translation of G1 cyclins in yeast, especially Cln3. There remains no evidence in yeast for regulation in the reverse direction, in which cell-cycle control machinery also regulates growth. Prober and Edgar review the evidence for this in Drosophila. It should be pointed out that this kind of control has not been exhaustively sought in yeast, although the literature does suggest that rather high rates of cell growth in yeast can persist in the absence of a functioning cell cycle. Perhaps the most basic aspect of cell growth is the generation of ATP from oxidation of carbohydrates; a critical requirement for tumors is thus oxygen. Different aspects of this problem are discussed in two reviews. Ivan and Kaelin (pp 27–34) review work on the Von Hippel–Lindau tumor suppressor, which may help block tumor formation by assembling multiprotein complexes that catalyze the ubiquitination and degradation of an oxygen-regulated transcription factor. Higher levels of this factor can lead to expression of angiogenesis-inducing genes. Giordano and Johnson (pp 35–40) review tumor angiogenesis in general. There are many aspects to the interaction of tumor cells with their environment in addition to achieving an adequate oxygen supply. The cancer cell interacts with its microenvironment by cytoskeletal changes leading to altered integrin–extracellular-matrix interactions. The cytoskeleton is also coregulated with complex intracellular signal-transduction pathways affecting many aspects of cell growth and gene expression. These issues are discussed in reviews by Pawlak and Helfman (pp 41–47), and Assoian and Schwartz (pp 48–53). Beyond interactions with extracellular components, tumor cells must interact with neighboring normal cells. This is an extremely complex, underexplored and underappreciated aspect of tumor biology. There is considerable evidence, reviewed by Tlsty and Hein (pp 54–59), that reciprocal interactions between tumor cells and the surrounding stromal cells makes critical contributions to the evolution of the tumor phenotype. This group of reviews suggests that a more complete understanding of tumor biology will require that we view the tumor not as a collection of autonomous, rogue cells
12
Oncogenes and cell proliferation
but rather as an organ composed of interdependent parts — tumor cells, blood vessels and stroma. This view of tumor biology justifies the application of more global approaches toward identifying changes in gene expression that contribute to the tumor phenotype. Rather than trying to understand tumorigenesis ‘one gene at a time’ it is clear that we now need to explore the idea of characterizing tumor progression in terms of large-scale changes in gene expression. This approach is reviewed by Porter (pp 60–63), who describes recent progress in the application of DNA microarrays to the analysis of human tumors. There is considerable evidence now that in addition to modulating cell growth rates, oncogenic mutations may also impinge directly on cell-cycle machinery. The gene for SV40 T antigen is one of the earliest described genetic inducers of cancer. Along with its abilities to interfere with cell regulatory machinery such as the Rb pathway, T antigen also participates directly in SV40 DNA replication, serving as the origin-binding protein as well as a replicative helicase. It is plausible that this serves the virus well by removing potential cellular controls on replication. At least in yeast, it is clear that the origin-binding aspect of T antigen is provided for cellular origins by the origin recognition complex, perhaps in combination with Cdc6. The cellular replicative helicase equivalent to T antigen has been harder to pin down. The review by Labib and Diffley (pp 64–70) focuses on the question of whether the MCM (minichromosome maintenance) complex is a good candidate for this helicase. Although some evidence supports this idea, the case is not closed, and Labib and Diffley (pp 64–70) ultimately raise the question of whether an exact equivalent to the T antigen function exists for cellular DNA replication. To date, aside from the SV40 example, there is no evidence for oncogenic stimuli directly targeting or co-opting DNA replication machinery, and thus DNA replication may be an example of a part of the cell-cycle machinery that is only indirectly activated by oncogenesis. New insights into regulation of the chromosomal helicase, be it the MCM complex or something else, should help to resolve this important question. A key aspect to keeping cell cycles orderly is constituted by the surveillance mechanisms or checkpoints that probably function to prevent aneuploidy and other errors in division. These checkpoints are important in regulating cancer because such errors in division are probably central to generating mutations that can affect cell growth and cell-cycle control. There are two main branches of checkpoint control: one monitoring spindle function, and one monitoring DNA damage. Much work has implicated derangements of both checkpoints in oncogenesis. The
involvement of ATM-related protein kinases in the DNA damage checkpoint is reviewed in mammalian systems by Shiloh (pp 71–77), and the regulation by these kinases and others of the Chk1–Cds1–Cdc25 system in yeast — many but not all aspects of which appear to be conserved in mammalian cells — is reviewed by Walworth (pp 78–82). Wassman and Benezra (pp 83–90) review the spindle checkpoint from basic biology to cancer. Lastly we turn to the question of how tumor cells override the normal physiological limitations on cell division. These limitations are imposed by two general processes. First is the limitation imposed by programs of cellular differentiation, and second is the ultimate restriction facing cell division — the universal program of cellular senescence. Thus, tumorigenesis does not only involve the inappropriate expression of extrinsic and intrinsic signals that promote cell growth and proliferation. It is also accompanied by mechanisms that override cellular programs for terminal phenotypic differentiation, and by cellular changes that permit clonal expansion beyond the cell’s normally limited lifespan. Zhu and Skoultchi (pp 91–97) discuss the fact that functional differentiation almost always involves the cessation of cell division and, in this context, review evidence that cell-cycle regulatory proteins may themselves regulate cellular differentiation. Changes in certain cell-cycle regulators can allow differentiated cells to proliferate well beyond their normal capacity to do so, and this may have important implications for the origin of tumor cells. Wright and Shay (pp 98–103) review evidence that telomere attrition is the mechanism underlying cellular senescence and evidence that activation of telomerase is sufficient, on its own, for cells to overcome the senescence-induced blockade to proliferation. They suggest that the counter-examples of human epithelial cells and murine fibroblasts, which undergo senescence in vitro despite expression of active telomerase, are not exceptions to this general principle but rather represent artifacts of cell culture. It is obviously of essential practical concern to use the information generated by our studies of tumor biology to learn how better to eradicate the disease in patients. Huang and Oliff (pp 104–110) describe one important approach toward the development of new targeted attacks on tumor cells by incorporating the particular genetic and molecular features of cancer cells into the design of specialized anti-tumor drugs. This review is intended to stimulate the research community into thinking about how the progress being made in understanding tumor biology could be applied in a rational way to the design of better therapeutic agents.