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The Cell Cycle: Myths and Realities Renato Baserga1

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The Cell Cycle: Myths and Realities Renato Baserga1 [CANCER RESEARCH 50, 6769-6771, November 1, 1990] Perspectives in Cancer Research The Cell Cycle: Myths and Realities Renato Baserga1 Department of Pathology and the Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 A number of startling discoveries in the past few years have simply overexpression, the regulation of cell growth is affected. given us a picture of the cell cycle that is solidly based on Indeed, even now, despite antioncogenes and yeast genes, one molecular biology and genetics. Growth factors (both stimula cannot disregard protooncogenes in any rational scheme of tory and inhibitory), oncogenes and antioncogenes, the bio animal cell proliferation. The extent of their role may be chemistry of DNA replication, the animal homologues of yeast debatable, but they do have a role. However, their putative cell cycle genes, cyclins, the use of antisense strategies, and growth-regulatory role is based on their relationship to viral many others have opened new vistas to our understanding of transforming genes and not on the fact that they are growth cell cycle controls (1). This perspective, however, is not dedi regulated. cated to a eulogy of these seminal findings; they speak for In the meantime, scores of laboratories (including mine, I themselves. I will, in fact, be the devil's advocate and do the admit) have been picking out, through differential screening of opposite, i.e., have a critical look, not at the findings (they are complementary DNA libraries, an embarrassing number of unarguable), but at some of the conclusions that have been growth-regulated genes. At first, genes the expression of which drawn from these findings. I wish to make myself very clear: increases early in G, (after stimulation of G0 cells) were most there has been a revolution in the past 10 years in our under popular but, more recently, growth-regulated genes at the d-S standing of the cell cycle, a revolution supported by findings boundary have become fashionable. In many instances, the the importance of which cannot be exaggerated. And most of announcement of the discovery of a new growth-regulated gene us have been guarded in our conclusions. But as it happens is accompanied by more or less bold comments about its im often in science, a timid suggestion at the end of a discussion, portant role in the control of cell proliferation. It is time that a carefully worded hypothesis, become transformed in the next this myth be put to rest for two reasons: (a) the expression of paper (often by other authors) into a fact. Thus, a simple some growth-regulated genes and oncogenes is also induced in statement like "gene X may play a role in cell proliferation" situations in which cell proliferation does not occur, or, indeed, becomes in the next paper "gene X is growth regulatory." It is may even be inhibited, for instance, c-fos (5); and (b) more not surprising, therefore, that this transforming capacity of important, some exquisitely growth-regulated genes do not have words has given rise to a number of interpretations of cell cycle any growth-regulatory function. The best example is the thy- events, interpretations that are clearly extrapolations of the midine kinase (TK) gene: growing cells can do without TK; indeed, there are animals whose cells are all TK~ without, facts, and that I have elected, in this perspective, to call myths. It is some of these myths that I would like to discuss here, not obviously, affecting their growth (6). Conclusion: a growth- to pour water on our enthusiasm (which is justified) but for the regulated gene is a growth-regulated gene. To become growth purpose of placing our understanding of the cell cycle back to regulatory it must meet other criteria. its proper perspective, which in simple terms, is: "there are many things that control cell proliferation and they have not all been sorted out." This may seem obvious; yet some of the Myth 2: What's Going On in My Cells Is Universal and Is the comments we have read recently in scientific journals are far Only Truth from following this maxim. Let us look at some of these myths. Probably all of us, at one time or another, commit this sin. Most of us repent quickly; others persist obstinately in their parochial views. The myth takes many forms. For instance, Myth 1: Growth-regulated Genes Are Growth Regulatory some years ago, there was a lot of resistance to the concept that the 5'-flanking sequence of the TK gene plays a major role in This is one of the most common and persistent myths. It began several years ago when it was shown that certain pro- the control of TK expression in fibroblasts. The opposition tooncogenes were growth regulated, i.e., that the steady state came mostly from people working with muscle cells, where the mRNA levels of some protooncogenes increased when quies regulation of TK expression is totally different. The point is cent cells (usually fibroblasts or lymphocytes) were stimulated that, in this instance, both parties were right; it just happens to proliferate by growth factors. The first two protooncogenes that fibroblasts and muscle cells have their own particular ways that were shown to be growth regulated were c-myc (2) and c- of regulating TK expression. Jt s (3), but several others (c-fgr, c-myb, c-ets-l, etc.) have been There are many other examples: (a) c-myb clearly plays a added since then (4). role in the proliferation of hemopoietic cells (7), but fibroblasts The extrapolation from growth regulated to growth regula completely ignore it, and even v-myb (with its long terminal tory was, in some respects, justified. After all, protooncogenes repeat) cannot transform fibroblasts; (b) the classical growth- must have something to do with the control of cellular prolif regulated genes of fibroblasts and lymphocytes (c-fos, c-myc, eration, since, when the expression or activity of a protoonco etc.) are not growth regulated in alveolar lung epithelial cells, gene is modified by mutations, translocations, amplification, or or, at least, their mRNA levels are not growth regulated, al though their proteins are (8); (c) HeLa cells, very popular in Received 5/11/90; accepted 8/2/90. ' To whom requests for reprints should be addressed, at Department of many laboratories, are often presented as model cells for cell Pathology, Temple University School of Medicine, 3420 N. Broad Street, Phila cycle regulation of gene expression. Mind you, there is nothing delphia, PA 19140. wrong with the data. I have no doubts that gene expression in 6769 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1990 American Association for Cancer Research. THE CELL CYCLE HeLa cells is regulated as advertised. Perhaps, normal cells, more than one growth-regulatory gene, in other words, that T- i.e., cells with growth controls, have different ways of doing antigen and the EIA protein unite, in a single gene product, things ... ; (d) if what's going on in HeLa cells is perhaps more information that, in the normal cell, is divided between two or the exception than the rule, can you imagine making the oocyte more genes. I would be willing, in the meantime, to bestow on a model of cell cycle regulation? A cell already full of all the c-myc the title of (incomplete) growth-regulatory gene. Inciden RNAs and proteins that are necessary for cell growth? A cell tally, \-onc do not count; what we are after here are normal, that, fertilized, can grow up to the stage of gastrula without cellular genes that regulate normal cell growth. synthesizing rRNA? Try to inhibit rRNA synthesis in somatic Where does this leave the oncogenes (besides c-myc)1! As cells: they stop cold; they won't even go through one cycle of already mentioned above, protooncogenes, when suitably mod division. Again, what has been described in oocytes is wonderful ified, can alter the regulation of cell growth. If they only are work, but it applies to oocytes. Its extrapolation to somatic required, why would a mutation (for example) cause them to cells is premature. drive cellular proliferation abnormally? An explanation may be Conclusion: for 30 years I have taught my postdoctoral found in the following illustration: 32D myeloid cells do not fellows and graduate students that what we find in our cells have EGF receptors, are not stimulated by EGF, and have an applies only to our cells, under the conditions we used, at least absolute requirement for interleukin 3. However, if they carry until otherwise proved. It is a maxim that should have more the \-erb-B gene, which is a truncated, permanently activated general currency. EGF receptor, 32D myeloid cells can grow in the absence of interleukin 3 or other growth factors (12). It is as if their cell cycle had been short-circuited. Perhaps, in the case of protoon Myth 3: If Cell Proliferation Is Inhibited by an Antibody or an Antisense RNA to a Certain Gene Product, That Gene Product cogenes, their constitutive activation causes cells to progress is Growth Regulatory through the cell cycle in the absence of those gene products that in normal cells are required for their activation. This seems This statement is either a myth or a truth, depending on how to be the case with viral oncogenes: SV40 T-antigen and aden we define growth regulatory. ovirus EIA are known to activate G.-S boundary genes (like By now there are quite a few reports in the literature that TK, PCNA, etc.) in the absence of cellular products that are microinjected antibodies, or antisense RNA, or antisense oli- normally required by serum-stimulated cells; e.g., the products godeoxynucleotides can block cellular proliferation if targeted of early growth-regulated genes (13).
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