Cancer and the Immune System CHAPTER 22 503 which integrate randomly into the host chromosomal dna, gene and its corresponding proto-oncogene appear to have include several genes that are expressed early in the course of very similar functions. As described below, the conversion of viral replication. SV40 encodes two early proteins called large a proto-oncogene into an oncogene appears in many cases to Tand little T, and polyoma encodes three early proteins called accompany a change in the level of expression of a normal large T, middle T, and little T. Each of these proteins plays a growth-controlling protein. role in the malignant transformation of virus-infected cells Most RNa viruses replicate in the cytosol and do not Cancer-Associated Genes Have induce malignant transtormation. The exceptions are retro. Many Functions reverse-transcriptase enzyme and then integrate the tran- Homeostasis in normal tissue is maintained by a highly reg- script into the host's DNA. This process is similar in the cyto- ulated process of cellular proliferation balanced by cell death. pathic retroviruses such as HIV-1 and HIV-2 and in the If there is an imbalance, either at the stage of cellular prolif- transforming retroviruses, which induce changes in the host eration or at the stage of cell death, then a cancerous state will cell that lead to malignant transformation. In some cases, develop Oncogenes and tumor suppressor genes have been retrovirus-induced transformation is related to the presence shown to play an important role in this process, by regulating of oncogenes, or"cancer genes "carried by the retrovirus. either cellular proliferation or cell death. Cancer-associated One of the best-studied transforming retroviruses is the genes can be divided into three categories that reflect these Rous sarcoma virus. This virus carries an oncogene called different activities, summarized in Table 22-1 v-src, which encodes a 60-kDa protein kinase(v-Src)that cat- alyzes the addition of phosphate to tyrosine residues on pro- INDUCTION OF CELLULAR PROLIFERATION teins. The first evidence that oncogenes alone could induce One category of proto-oncogenes and their oncogenic coun- malignant transformation came from studies of the v-src on- terparts encodes proteins that induce cellular proliferation. gene from Rous Sarcoma virus When this oncogene was Some of these proteins function as growth factors or growth cloned and transfected into normal cells in culture, the cells factor receptors. Included among these are sis, which encodes underwent malignant transformation. a form of platelet-derived growth factor, and fms, erbB, and neu,which encode growth-factor receptors. In normal cells, the expression of growth factors and their receptors is care- Oncogenes and Cancer Induction fully regulated. Usually, one population of cells secretes a growth factor that acts on another population of cells that In 1971, Howard Temin suggested that oncogenes might not tion of the second population. Inappropriate expression of rries the receptor for the factor, thus stimulating prolifera- normal cells; indeed, he proposed that a virus might acquire either a growth factor or its receptor can result in uncon- oncogenes from the genome of an infected cell. He called trolled proliferation. these cellular genes proto-oncogenes, or cellular oncogenes Other oncogenes in this category encode products tha (c-onc, to distinguish them from their viral counterparts function in signal-transduction pathways or as transcription (v-onc). In the mid-1970s, I.M. Bishop and H. E Varmus factors. The src and abl oncogenes encode tyrosine kinases, identified a DNA sequence in normal chicken cells that is and the ras oncogene encodes a GTP-binding protein.The homologous to v-src from Rous sarcoma virus. This cellular products of these genes act as signal transducers. The myc, oncogene was designated c-src. Since these early discoveri jun, and fos oncogenes encode transcription factors. Overac numerous cellular oncogenes have been identified. tivity of any of these oncogenes may result in unregulated uence comparisons of viral and cellular oncogenes proliferation. reveal that they are highly conserved in evolution. Although most cellular oncogenes consist of a series of exons and in- INHIBITION OF CELLULAR PROLIFERATION trons, their viral counterparts consist of uninterrupted cod- A second category of cancer-associated genes-called tumor ing sequences, suggesting that the virus might have acquired suppressor genes, or anti-oncogenes-encodes proteins that the oncogene through an intermediate RNA transcript from hich the intron sequences had been removed during RNa sults in unregulated proliferation. The prototype of this cate processing. The actual coding sequences of viral oncogenes gory of oncogenes is Rh, the retinoblastoma gene Hereditary and the corresponding proto-oncogenes exhibit a high de- retinoblastoma is a rare childhood cancer, in which tumors gree of homology; in some cases, a single point mutation is develop from neural precursor cells in the immature retina. all that distinguishes a viral oncogene from the correspond- The affected child has inherited a mutated Rb allele; somatic ing proto-oncogene. It has now become apparent that most, inactivation of the remaining Rballele leads to tumor growth. if not all, oncogenes(both viral and cellular)are derived from Probably the single most frequent genetic abnormality in cellular genes that encode various growth-controlling pro- human cancer is mutation in p53, which encodes a nuclear teins. In addition, the proteins encoded by a particular onco- phosphoprotein. Over 90% of small-cell lung cancers andwhich integrate randomly into the host chromosomal DNA, include several genes that are expressed early in the course of viral replication. SV40 encodes two early proteins called large T and little T, and polyoma encodes three early proteins called large T, middle T, and little T. Each of these proteins plays a role in the malignant transformation of virus-infected cells. Most RNA viruses replicate in the cytosol and do not induce malignant transformation. The exceptions are retro￾viruses, which transcribe their RNA into DNA by means of a reverse-transcriptase enzyme and then integrate the tran￾script into the host’s DNA. This process is similar in the cyto￾pathic retroviruses such as HIV-1 and HIV-2 and in the transforming retroviruses, which induce changes in the host cell that lead to malignant transformation. In some cases, retrovirus-induced transformation is related to the presence of oncogenes, or “cancer genes,” carried by the retrovirus. One of the best-studied transforming retroviruses is the Rous sarcoma virus. This virus carries an oncogene called v-src,which encodes a 60-kDa protein kinase (v-Src) that cat￾alyzes the addition of phosphate to tyrosine residues on pro￾teins. The first evidence that oncogenes alone could induce malignant transformation came from studies of the v-src on￾cogene from Rous sarcoma virus. When this oncogene was cloned and transfected into normal cells in culture, the cells underwent malignant transformation. Oncogenes and Cancer Induction In 1971, Howard Temin suggested that oncogenes might not be unique to transforming viruses but might also be found in normal cells; indeed, he proposed that a virus might acquire oncogenes from the genome of an infected cell. He called these cellular genes proto-oncogenes, or cellular oncogenes (c-onc), to distinguish them from their viral counterparts (v-onc). In the mid-1970s, J. M. Bishop and H. E. Varmus identified a DNA sequence in normal chicken cells that is homologous to v-src from Rous sarcoma virus. This cellular oncogene was designated c-src. Since these early discoveries, numerous cellular oncogenes have been identified. Sequence comparisons of viral and cellular oncogenes reveal that they are highly conserved in evolution. Although most cellular oncogenes consist of a series of exons and in￾trons, their viral counterparts consist of uninterrupted cod￾ing sequences, suggesting that the virus might have acquired the oncogene through an intermediate RNA transcript from which the intron sequences had been removed during RNA processing. The actual coding sequences of viral oncogenes and the corresponding proto-oncogenes exhibit a high de￾gree of homology; in some cases, a single point mutation is all that distinguishes a viral oncogene from the correspond￾ing proto-oncogene. It has now become apparent that most, if not all, oncogenes (both viral and cellular) are derived from cellular genes that encode various growth-controlling pro￾teins. In addition, the proteins encoded by a particular onco￾gene and its corresponding proto-oncogene appear to have very similar functions. As described below, the conversion of a proto-oncogene into an oncogene appears in many cases to accompany a change in the level of expression of a normal growth-controlling protein. Cancer-Associated Genes Have Many Functions Homeostasis in normal tissue is maintained by a highly reg￾ulated process of cellular proliferation balanced by cell death. If there is an imbalance, either at the stage of cellular prolif￾eration or at the stage of cell death, then a cancerous state will develop. Oncogenes and tumor suppressor genes have been shown to play an important role in this process, by regulating either cellular proliferation or cell death. Cancer-associated genes can be divided into three categories that reflect these different activities, summarized in Table 22-1. INDUCTION OF CELLULAR PROLIFERATION One category of proto-oncogenes and their oncogenic coun￾terparts encodes proteins that induce cellular proliferation. Some of these proteins function as growth factors or growth￾factor receptors. Included among these are sis, which encodes a form of platelet-derived growth factor, and fms, erbB, and neu, which encode growth-factor receptors. In normal cells, the expression of growth factors and their receptors is care￾fully regulated. Usually, one population of cells secretes a growth factor that acts on another population of cells that carries the receptor for the factor, thus stimulating prolifera￾tion of the second population. Inappropriate expression of either a growth factor or its receptor can result in uncon￾trolled proliferation. Other oncogenes in this category encode products that function in signal-transduction pathways or as transcription factors. The src and abl oncogenes encode tyrosine kinases, and the ras oncogene encodes a GTP-binding protein. The products of these genes act as signal transducers. The myc, jun, and fos oncogenes encode transcription factors. Overac￾tivity of any of these oncogenes may result in unregulated proliferation. INHIBITION OF CELLULAR PROLIFERATION A second category of cancer-associated genes—called tumor￾suppressor genes, or anti-oncogenes—encodes proteins that inhibit excessive cell proliferation. Inactivation of these re￾sults in unregulated proliferation. The prototype of this cate￾gory of oncogenes is Rb, the retinoblastoma gene. Hereditary retinoblastoma is a rare childhood cancer, in which tumors develop from neural precursor cells in the immature retina. The affected child has inherited a mutated Rb allele; somatic inactivation of the remaining Rb allele leads to tumor growth. Probably the single most frequent genetic abnormality in human cancer is mutation in p53, which encodes a nuclear phosphoprotein. Over 90% of small-cell lung cancers and Cancer and the Immune System CHAPTER 22 503