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本课件为《分子生物学》第28章癌基因与癌症（Oncogenes and cancer），依据 Gene VII 编排，讲解本章核心概念与分子机制，配逐页图示与文字版。
Chapter 28 Oncogenes and cancer
Aneuploid chromosome constitution differs from the usual diploid constitution by loss or duplication of chromosomes or chromosomal segments.
Figure 28.1 Three types of properties distinguish a cancer cell from a normal cell. Sequential changes in cultured cells can be correlated with changes in tumorigenicity.
Figure 28.1 Three types of properties distinguish a cancer cell from a normal cell. Sequential changes in cultured cells can be correlated with changes in tumorigenicity.
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Figure 28.2 Normal fibroblasts grow as a layer of flat, spread-out cells, whereas trans formed fibroblasts are rounded up and grow in cell masses. The cultures on the left contain normal cells, those on the right contain trans formed cells. The top views are by conventional microscopy, the bottom by scanning electron microscopy. Photographs kindly provided by Hidesaburo Hanafusa and J. Michael Bishop.
Figure 28.3 Transforming viruses may carry oncogenes.
Figure 28.4 Permissive cells are productively infected by a DNA tumor virus that enters the lytic cycle, while nonpermissive cells are trans formed to change their phenotype.
Figure 28.5 Cells trans formed by polyom a viruses or adenovir uses have viral sequences that include the early region integrated into the cellular genome. Sites of integr at ion are random.
Figure 28.6 Retroviruses transfer genetic information horizontally by infecting new hosts; information is inherited vertically if a virus integrates in the genome of the germline.
Figure 16.2 The retroviral life cycle proceeds by reverse transcribing the RNA genome into duplex DNA, which is inserted into the host genome, in order to be transcribed into RNA.
Figure 28.7 A transforming retrovirus carries a copy of a cellular sequence in place of some of its own gene(s).
Proto-oncogenes are the normal counterparts in the eukaryotic genome to the oncogenes carried by some retroviruses. They are given names of the form c-onc .
Figure 28.8 Each transforming retrovirus carries an oncogene derived from a cellular gene. Viruses have names and abbrevi at ions reflecting the history of their isol at ion and the types of tumor they cause. This list shows some representative examples of the retroviral oncogenes.
Figure 28.8 Each transforming retrovirus carries an oncogene derived from a cellular gene. Viruses have names and abbrevi at ions reflecting the history of their isol at ion and the types of tumor they cause. This list shows some representative examples of the retroviral oncogenes.
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Figure 28.8 Each transforming retrovirus carries an oncogene derived from a cellular gene. Viruses have names and abbrevi at ions reflecting the history of their isol at ion and the types of tumor they cause. This list shows some representative examples of the retroviral oncogenes.
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Figure 28.9 The transfection assay allows (some) oncogenes to be isolated directly by assaying DNA of tumor cells for the ability to trans form normal cells into tumorigenic cells.
Figure 28.9 The transfection assay allows (some) oncogenes to be isolated directly by assaying DNA of tumor cells for the ability to trans form normal cells into tumorigenic cells.
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Figure 28.8 Each transforming retrovirus carries an oncogene derived from a cellular gene. Viruses have names and abbrevi at ions reflecting the history of their isol at ion and the types of tumor they cause. This list shows some representative examples of the retroviral oncogenes.
Figure 28.10 Pathways that rely on Ras could function by controlling either GNRF or GAP. Oncogenic Ras mutants are refractory to control, because Ras remains in the active form.
Reciprocal translocation exchanges part of one chromosome with part of another chromosome.
Figure 17.29 Amplified copies of the dhfr gene produce a homogeneously staining region (HSR) in the chromosome. Photograph kindly provided by Robert Schimke.
Figure 17.30 Amplified extrachromosomal dhfr genes take the form of double-minute chromosomes, as seen in the form of the small white dots. Photograph kindly provided by Robert Schimke.
Figure 28.11 Insertions of ALV at the c-myc locus occur at various positions, and activate the gene in different ways.
Figure 28.12 A chromosomal translocation is a reciprocal event that exchanges parts of two chromosomes. Trans locations that activate the human c-myc proto-oncogene involve Ig loci in B cells and TcR loci in T cells.
Figure 28.12 A chromosomal translocation is a reciprocal event that exchanges parts of two chromosomes. Trans locations that activate the human c-myc proto-oncogene involve Ig loci in B cells and TcR loci in T cells.
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Figure 28.13 Trans locations between chromosome 22 and chromosome 9 generate Philadelphia chromosomes that synthesize bcr-abl fusion transcripts that are responsible for two types of leukemia.
Figure 28.14 Oncogenes may code for secreted proteins, transmembrane proteins, cytoplasmic proteins, or nuclear proteins.
Figure 28.14 Oncogenes may code for secreted proteins, transmembrane proteins, cytoplasmic proteins, or nuclear proteins.
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Figure 28.14 Oncogenes may code for secreted proteins, transmembrane proteins, cytoplasmic proteins, or nuclear proteins.
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Figure 26.14 Binding of ligand to the extracellular domain can induce aggreg at ion in several ways. The common feature is that this causes new contacts to form between the cytoplasmic domains.
Figure 28.15 Activation of a growth factor receptor involves ligand binding, dimerization, and autophosphoryl at ion. A truncated oncogenic receptor that lacks the ligand-binding region is constitutively active because it is not repressed by the N-terminal domain.
Figure 28.14 Oncogenes may code for secreted proteins, transmembrane proteins, cytoplasmic proteins, or nuclear proteins.
Figure 28.16 A Src protein has an N-terminal domain that associates with the membrane, a modulatory domain that includes SH2 and SH3 motifs, a kinase catalytic domain, and (c-Src only) a suppressor domain.
Figure 28.17 Two tyrosine residues are targets for phosphorylation in Src proteins. Phosphorylation at Tyr-527 of c-Src suppresses autophosphoryl at ion at Tyr-416, which is associated with transforming activity. Only Tyr-416 is present in v-Src. Transforming potential of c-Src may be activated by removing Tyr-527 or repressed by removing Tyr-416.
Figure 28.18 When a receptor tyrosine kinase is activated, autophosphoryl at ion generates a binding site for the Src SH2 domain, Tyr-527 is released and dephosphorylated, Tyr-416 becomes phosphorylated, and Src kinase is activated.
Figure 28.19 Oncogenes that code for transcription factors have mutations that inactivate transcription (v-erbA and possibly v-rel) or that activate transcription (v-jun and v-fos).
Figure 28.19 Oncogenes that code for transcription factors have mutations that inactivate transcription (v-erbA and possibly v-rel) or that activate transcription (v-jun and v-fos).
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Figure 28.19 Oncogenes that code for transcription factors have mutations that inactivate transcription (v-erbA and possibly v-rel) or that activate transcription (v-jun and v-fos).
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Figure 28.20 The adenovirus E1A region is spliced to form three transcripts that code for overlapping proteins. Domain 1 is present in all proteins, domain 2 in the 289 and 243 residue proteins, and domain 3 is unique to the 2 The adenovirus E1A region is spliced to form three transcripts that code for overlapping proteins. Domain 1 is present in all proteins, domain 2 in the 289 and 243 residue proteins, and domain 3 is unique to the 289 residue protein. The C-terminal domain of the 55 residue protein is translated in a different reading frame from the common C-terminal domains of the other two proteins.
Figure 28.21 Retinoblastoma is caused by loss of both copies of the RB gene in chromosome band 13q14. In the inherited form, one chromosome has a deletion in this region, and the second copy is lost by somatic mutation in the individual. In the sporadic form, both copies are lost by individual somatic events.
Figure 28.21 Retinoblastoma is caused by loss of both copies of the RB gene in chromosome band 13q14. In the inherited form, one chromosome has a deletion in this region, and the second copy is lost by somatic mutation in the individual. In the sporadic form, both copies are lost by individual somatic events.
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Figure 28.22 A block to the cell cycle is released when RB is phosphorylated (in the normal cycle) or when it is sequestered by a tumor antigen (in a trans formed cell).
Figure 28.23 Several components concerned with G0/G1 or G1/S cycle control are found as tumor suppressors.
Figure 28.24 Wild-type p53 is required to restrain cell growth. Its activity may be lost by deletion of both wild-type alleles or by a dominant mutation in one allele.
Figure 28.24 Wild-type p53 is required to restrain cell growth. Its activity may be lost by deletion of both wild-type alleles or by a dominant mutation in one allele.
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Figure 28.25 Damage to DNA activates p53. The outcome depends on the stage of the cell cycle. Early in the cycle, p53 activates a checkpoint that prevents further progress until the damage has been repaired. If it is too late to exercise the checkpoint, p53 triggers apoptosis.
Figure 28.26 Different domains are responsible for each of the activities of p53.
Figure 28.26 Different domains are responsible for each of the activities of p53.
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Figure 28.27 53 activates several independent pathways. Activation of cell cycle arrest together with inhibition of genome instability is an alternative to apoptosis.
Figure 27.25 p21 and p27 inhibit assembly and activity of cdk4,6-cyclin D and cdk2-cyclin E by CAK. They also inhibit cycle progression independent of RB activity. p16 inhibits both assembly and activity of cdk4,6-cyclin D.
Figure 28.23 Several components concerned with G0/G1 or G1/S cycle control are found as tumor suppressors.
Figure 28.28 p53 activity is antagonized by mdm2, which is neutralized by p19 ARF.
Figure 28.29 Each pathway that activates p53 causes modification of a particular set of residues.
Most tumors arise as the result of multiple events. It is likely that some of these events involve the activation of oncogenes, while others take the form of inactiv at ion of tumor suppressors. The requirement for multiple events reflects the fact that normal cells have multiple mechanisms to regulate their growth and differenti at ion, and several separate changes may be required to bypass these controls.
Indeed, the existence of many genes in which single mutations were tumorigenic would no doubt be deleterious to the organism, and has been selected against. None the less, oncogenes and tumor suppressors define genes in which mutations create a pred is position to tumors, that is, they represent one of the necessary events.
It is an open questi on as to whether the oncogenes and tumor suppressor genes identified in available assays are together sufficient to account entirely for the occurrence of cancers, but it is clear that their properties explain at least many of the relevant events.
1.A tumor cell is distinguished from a normal cell by its immortality, morphological trans formation, and (sometimes) ability to metast a size. 2.DNA tumor viruses carry oncogenes without cellular counterparts. 3.Some v-onc genes are qualitatively different from their c-onc counterparts, since the v-onc gene is oncogenic at low levels of protein, while the c-onc gene is not active even at high levels.4. c-onc genes have counterpart v-onc genes in retroviruses, but some proto-oncogenes have been identified only by their association with cellular tumors.
5.Cellular oncoproteins may be derived from several types of genes. 6.Growth factor receptors located in the plasma membrane are represented by truncated versions in v-onc genes. 7.Some oncoproteins are cytoplasmic tyrosine kinases; their targets are largely unknown. 8.Ras proteins can bind GTP and are related to the subunits of G proteins involved in signal transduction across the cell membrane.
9.Nuclear oncoproteins may be involved directly in regulating gene expression, and include Jun and Fos, which are part of the AP1 transcription factor.10.Retinoblastoma (RB) arises when both copies of the RB gene are deleted or inactivated.11.p53 was originally classified as an oncogene because missense mutations in it are oncogenic. 12.p53 has a sequence-specific DNA-binding domain that recognizes a palindromic ~10 bp sequence.
13.p53 is bound by viral oncogenes such as SV40 T antigen, whose oncogenic properties result, at least in part, from the ability to block p53 function. 14.The locus INK4A contains two tumor suppressors that together control both major tumor suppressor pathways. 15.Loss of p53 may be necessary for immortaliz at ion, because both the G1 checkpoint and the trigger for apoptosis are inactivated.
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