癌基因抑癌基因與生長因子精選PPT

1、關(guān)于癌基因抑癌基因與生長因子第一張，PPT共一百五十五頁，創(chuàng)作于2022年6月 細胞的正常生長與增殖由兩大類基因調(diào)控：正調(diào)節(jié)信號 促進細胞生長和增殖，并阻止其發(fā)生終末分化。負調(diào)控信號 抑制增殖, 促進分化、成熟和衰老，最后凋亡。這兩類基因中任何一種或它們共同的變化，即有可能引起細胞增殖失控導(dǎo)致腫瘤的發(fā)生。第二張，PPT共一百五十五頁，創(chuàng)作于2022年6月癌基因與抑癌基因的作用機制涉及基因表達調(diào)控及細胞分裂、分化。癌基因可編碼類生長因子多肽及其受體分子，通過細胞內(nèi)信息傳遞系統(tǒng)刺激細胞增殖。腫瘤的發(fā)生與癌基因、抑癌基因和生長因子三者的關(guān)系密切相關(guān)。第三張，PPT共一百五十五頁，創(chuàng)作于2022年6月

2、第一節(jié) 癌基因第四張，PPT共一百五十五頁，創(chuàng)作于2022年6月癌基因（oncogene）就是具有增加癌源性或轉(zhuǎn)化潛能，導(dǎo)致其編碼區(qū)或調(diào)節(jié)區(qū)域遺傳性狀發(fā)生改變的基因。癌基因可分為兩大類：一類是致瘤病毒中能在體內(nèi)誘發(fā)腫瘤并在體外引起細胞轉(zhuǎn)化的基因，即病毒癌基因（viral oncogene, v-onc）；另一類是存在于細胞基因組中、正常情況下處于靜止或低水平（限制性）表達狀態(tài)，對維持細胞正常功能具有重要作用，當(dāng)受到致癌因素作用被活化而導(dǎo)致細胞惡變的基因，即原癌基因（protooncogene，pro-onc）或稱細胞癌基因（cellular oncogene，c-onc）。一、病毒癌基因和細胞

3、癌基因 （一）概念第五張，PPT共一百五十五頁，創(chuàng)作于2022年6月 癌基因名稱用3個斜體小寫字母表示，如myc、ras、src。腫瘤病毒是一類能使宿主產(chǎn)生腫瘤或使培養(yǎng)細胞轉(zhuǎn)化成癌細胞的動物病毒。其核酸組成分為DNA病毒和RNA病毒。病毒癌基因是一類存在于腫瘤病毒（大多數(shù)是逆轉(zhuǎn)錄病毒）中的、能使靶細胞發(fā)生惡性轉(zhuǎn)化的基因。第六張，PPT共一百五十五頁，創(chuàng)作于2022年6月 1911年， Reyton Rous 報道將雞肉瘤的無細胞濾液注射給健康雞后，可誘導(dǎo)發(fā)生肉瘤，表明無細胞濾液含致病原，可傳播腫瘤。1932年，Shope發(fā)現(xiàn)，野生棉尾兔的皮膚腫瘤也可借助無細胞濾液傳播。腫瘤進展：開始，癌細胞處

4、于“休眠”狀態(tài)，被化學(xué)因子、病毒等喚醒后，變的無法無天。Rous提出病毒致癌理論：即傳播腫瘤的無細胞濾液中含的是病毒。這種感染性顆粒后來被證實是逆轉(zhuǎn)錄病毒(RNA病毒)。Rous因此獲得1966年諾貝爾生理和醫(yī)學(xué)獎。癌基因的發(fā)現(xiàn)第七張，PPT共一百五十五頁，創(chuàng)作于2022年6月The Nobel Prize in Physiology or Medicine 1966 Tumor-inducing viruses第八張，PPT共一百五十五頁，創(chuàng)作于2022年6月Peyton RousUSARockefeller UniversityNew York, NY, USAB: 1879D:1970第

5、九張，PPT共一百五十五頁，創(chuàng)作于2022年6月雞肉瘤病毒（RSV)基因組結(jié)構(gòu)圖 病毒癌基因與正常細胞中的原癌基因同源第十張，PPT共一百五十五頁，創(chuàng)作于2022年6月 病毒癌基因致癌機制第十一張，PPT共一百五十五頁，創(chuàng)作于2022年6月1964年H.M.Temin認為，RSV的生活周期中存在著前病毒（provirus）的DNA中間產(chǎn)物階段，DNA前病毒含有RNA病毒基因組的全部信息。子代病毒RNA是以前病毒DNA為模版合成的。前病毒可整合到宿主細胞基因組中。通過病毒的誘導(dǎo)，正常細胞可轉(zhuǎn)化成腫瘤細胞。1970年Temin實驗室和Baltimove 實驗室分別發(fā)現(xiàn)RSV病毒粒子中含有反轉(zhuǎn)錄酶。

6、這一結(jié)果使Temin 的“前病毒”假想得到了證實。1975年Temin、Baltimove和Dulbacco因此獲諾貝爾生理和醫(yī)學(xué)獎。第十二張，PPT共一百五十五頁，創(chuàng)作于2022年6月The Nobel Prize in Physiology or Medicine 1975 The interaction between tumor viruses and the genetic material of the cell第十三張，PPT共一百五十五頁，創(chuàng)作于2022年6月David B BaltimoreUSAMassachusetts Institute ofTechnology (MI

7、T)Cambridge, MA, USAB: 1938第十四張，PPT共一百五十五頁，創(chuàng)作于2022年6月Renato DulbeccoUSAImperial Cancer ResearchFund LaboratoryLondon, United KingdomB: 1914 (in Catanzaro, Italy)第十五張，PPT共一百五十五頁，創(chuàng)作于2022年6月Howard Martin TeminUSAUniversity of WisconsinMadison, WI, USAB: 1934D: 1994第十六張，PPT共一百五十五頁，創(chuàng)作于2022年6月Bishop和Varmu

8、s等人于1980年提出了癌基因假說，認為Rous雞肉瘤病毒的致癌能力與病毒基因組的單個基因有關(guān)，即src基因。src基因本是正常細胞基因組的一部分(原癌基因），被病毒“劫持”后，病毒則具有致癌能力。原癌基因在正常細胞中的地位：調(diào)控細胞的分裂和生長。腫瘤細胞中癌基因的變化：過分活躍或突變，使其編碼產(chǎn)物改變。Bishop和Varmus獲1989年諾貝爾生理學(xué)和醫(yī)學(xué)獎第十七張，PPT共一百五十五頁，創(chuàng)作于2022年6月The Nobel Prize in Physiology or Medicine 1989 The cellular origin of retroviral oncogenes第十

9、八張，PPT共一百五十五頁，創(chuàng)作于2022年6月J. Michael BishopUSAUniversity of CaliforniaSchool MedicineSan Francisco, CA, USAB: 1936第十九張，PPT共一百五十五頁，創(chuàng)作于2022年6月Harold E. VarmusUSAUniversity of CaliforniaSchool of MedicineSan Francisco, CA, USAB: 1939第二十張，PPT共一百五十五頁，創(chuàng)作于2022年6月Press Release: The 1989 Nobel Prize in Physiol

10、ogy or MedicineNOBELFRSAMLINGEN KAROLINSKA INSTITUTETTHE NOBEL ASSEMBLY AT THE KAROLINSKA INSTITUTE9 October 1989 The Nobel Assembly at Karlinska Institute has today decided to award the Nobel Prize in Physiology or Medicine for 1989 jointly to J. Michael Bishop and Harold E. Varmusfor their discove

11、ry of the cellular origin of retroviral oncogenes. Press Release第二十一張，PPT共一百五十五頁，創(chuàng)作于2022年6月SummaryThe discovery awarded with this years Nobel Prize in Physiology or Medicine concerns the identification of a large family of genes which control the normal growth and division of cells. Distur-bances in

12、 one or some of these so-called oncogenes (Gk nco(s) Bulk , mass) can lead to transformation of a normal cell into a tumor cell and result in cancer.Michael Bishop and Harold Varmus used an oncogenic retrovirus to identify the growth-controlling oncogenes in normal cells. In 1976 they published the

13、remarkable conclusionthat the oncogene in the virus did not represent a true viral gene but instead was a normal cellular gene, which the virus had acquired during replication in the host cell and thereafter carried along. 第二十二張，PPT共一百五十五頁，創(chuàng)作于2022年6月Bishops and Varmus discovery of the cellular origi

14、n of retroviral oncogenes has had an extensive influence on the development of our knowledge about mechanisms for tumor development. Until now more than 40 different oncogenes have been demonstrated. The discovery has also widened our insight into the complicated signal systems which govern the norm

15、al growth of cells. Cellular Oncogenes Discovered by the Use of RetrovirusThe term oncogene was introduced in the middle of the 1960s to denote special parts of the genetic material of certain viruses. It was believed that this part of the genetic material could direct the transformation of a normal

16、 cell into a tumor cell under the influence of other parts of the viral genetic material, alternativelyvia chemical or physical effects. The favourite theory of the time was that virus-mediated cell-to-cell transmittance of oncogenes was the origin of all forms of cancer. This view was later proven

17、to be incorrect. 第二十三張，PPT共一百五十五頁，創(chuàng)作于2022年6月The original discovery of an oncogenic virus was made in 1916 by Peyton Rous working at the Rockefeller Institute in New York. Fifty years later Rous received the Nobel Prize in Physiology or Medicine. Rous virus, as the infectious agent later was named, i

18、s a member of a large virus family named retroviruses. The genetic material of these viruses is RNA (ribonucleic acid). This RNA can be transcribed into DNA (deoxyribonucleic acid) by a unique enzyme in the virus, reverse transcriptase. The 1975 Nobel Prize in Physiology or Medicine was awarded to D

19、avid Baltimore, Renato Dulbecco and Haward Temin partly for the discovery of this enzyme. Reverse transcription of the genetic material of the virus into DNA has the important consequence that it can become integrated into the chromosomal DNA in the cells. It was through investigations of Rous virus

20、 that this years laureates Michael Bishop and Harold Varmus in 1975 could demonstrate the true origin of oncogenes. They used one variant of Rous virus which contained an oncogenic gene (Figure 1) and another variant which lacked this gene. 第二十四張，PPT共一百五十五頁，創(chuàng)作于2022年6月By use of these viruses they man

21、aged to construct a nucleic acid probe which selectively identified the oncogene. This probe was used to search for the corresponding genetic material in DNA from different cells. It was then found that oncogene-like material could be detected in different species throughout the animal kingdom, in f

22、act even in simple organisms comprising only a few cells. Furthermore, it was shown that the gene had a fixed position in the chromosomes of a certain species, and that the gene, when it constituted part of the cellular genetic material, was divided into fragments (a mosaic gene) (Figure 1). Figure

23、1. The difference between an oncogene in a virus and in a cell. In retroviruses causing tumors there is a separate segment of transforming nucleic acid which has been derived from a cell. The cellular gene is split (a mosaic gene) whereas the oncogene in the virus is continuous.第二十五張，PPT共一百五十五頁，創(chuàng)作于2

24、022年6月These findings led to the remarkable conclusion that the oncogene in the virus did not represent a true viral gene but a cellular gene which the virus had picked up far back during its replication in cells and carried along. This cellular gene was found to have a central function in the cells.

25、 It controlled their growth and division. Through these studies of the abnormal, i.e. the diseased state, it was possible to elucidate critical normal cellular functions - a not uncommon situation in biomedical research. The original discovery of a cellular oncogene led to an intensive search for fu

26、rther similar genes. The explosive development of this field of research has led to the identification of more than 40 different oncogenes which direct different events in the complex signal systems that regulate the growth and division of cells. Changes in any one or more of these oncogenes may lea

27、d to cancer. 第二十六張，PPT共一百五十五頁，創(chuàng)作于2022年6月Balanced Cellular Interactions - A Biological WonderSymmetrical and asymmetrical, multicellular structures develop from the fertilized ovum by a process of differentiation about which only limited knowledge is available. In the fully developed individual caref

28、ully balanced conditions prevail. Damage of an organ elicits sophisticated repair processes which lead to restitution of the original condition of the organ. However, if a single cell escapes the network of growth control the result may be an abnormal local proliferation of cells or in the worst cas

29、e a cancer implying the dissemination of cells running amok. The development of a cancer is a complicated process involving several consecutive changes of the genetic material. Studies of cellular genes (proto-oncogenes) corresponding to the viral oncogenes, has started to shed light on the intricat

30、e systems which control normal cellular growth and division.第二十七張，PPT共一百五十五頁，創(chuàng)作于2022年6月Cellular Oncogene Products Constitute Links in Signal Chains which Regulate Growth and Division of Cells The regulation of growth and division of cells has turned out to be much more complicated than originally be

31、lieved. Cellular oncogene products with different properties act in different positions of elaborate signal systems (Figure 2). In order to transmit signals from one cell to the other or from one cell to itself there are growth factors. These factors appear in the fluids surrounding cells. There are

32、 examples of oncogene products, viz. proteins produced in the cytoplasm, which can act as growth factors. Thus, it was found that the product of the sis1) gene was closely related to a previously identified growth factor PDGF (Platelet Derived Growth Factor). 第二十八張，PPT共一百五十五頁，創(chuàng)作于2022年6月Figure 2. Onc

33、ogene products are links in signal chains that stretch from the cell surface to the genetic material in the cell nucleus. This chain is composed of (1) growth factors, (2) growth factor receptors, (3) signal transducing proteins in cell membranes, (4) phosphokinases in the cytoplasm and (5) proteins

34、 transported from the cytoplasm into the nucleus where they bind to DNA. The localization of different oncogene products (Sis, ErbB, Ras, Src, Myc) is schematically indicated. 第二十九張，PPT共一百五十五頁，創(chuàng)作于2022年6月In order for a growth factor to be able to interact with a cell there has to be membrane structur

35、es, receptors, to which they can bind. There are several oncogene products which represent receptors in the cytoplasmic membrane of the cells, e.g. ErbA, Fms, Kit. These receptors have a unique enzymatic activity. They are so-called kinases with a capacity to phosphorylate (=add a phosphate group) t

36、he amino acid tyrosine. There are two more groups of oncogene products with phosphokinase activity; firstly tyrosine/phospho-kinase which lack receptor function and is located at the inside of the cytoplasmic membrane, and secondly serine/threonine phosphokinase which is found in the cytoplasm. Thus

37、, oncogene products function as links in signal chains stretching from the surface of the cell to the genetic material in the nucleus. In the cytoplasm there is one more group of oncogene products. These are called Ras and are related to important cellular signal factors called G-proteins. Finally,

38、there is a large number of oncogene products which are located in the nucleus of the cell, i.e. Myc, Myb, Fos, ErbA and others. These products direct the transcription of DNA into RNA and therefore play a critical role in the selection of proteins to be synthesized by the cell. 第三十張，PPT共一百五十五頁，創(chuàng)作于20

39、22年6月Cancer - A Complex, Biological Sequence of EventsChanges in the genetic material constitute the basis for the development of all cancer. Generally there are several consecutive such changes which influence different steps in the signal chains described above. Therefore, one should priori not ex

40、pect to find one single clue to the mechanism of origin of cancer. However, application of the expanding knowledge in the oncogene field allows us to start comprehending the disharmonic orchestration behind abnormal cellular growth. It is conceptually incorrect to speak about cancer genes. However,h

41、istorical circumstances explain why the oncogene terminology was introduced before a designation of the corresponding normal cellular genes was proposed. From the point of view of cancer the important matter is to compare oncogenes in normal cells and in tumor cells. 第三十一張，PPT共一百五十五頁，創(chuàng)作于2022年6月Oncog

42、enes as a Cause of CancerThe majority of oncogenes have been discovered in experimental studies using retroviruses. However, in a few cases oncogenes were identified bythe use of an alternative technique, i.e. genetic material was isolated from tumor cells of non-viral origin and transferred (transf

43、ected) to other cells prapagated in culture. The cells receiving the DNA changed growth pattern, and further characterization of the transfected genetic material revealed the presence of oncogenes. Two principally different forms of activation of oncogenes can be distinguished. Firstly, the normal c

44、ellular oncogene is hyperactive, and secondly the oncogene product is altered so that it can no longer be regulated in a normal way. There are several examples of these types of activation of oncogenes. The discovery of oncogenes was as mentioned originally made by the use of retroviruses. This infe

45、rs that genetic control elements in the virus itself can be responsible for the abnormal expression of the oncogene. However, in many cases it was found that alterations of the transferred oncogene contributed to its accentuated expression. 第三十二張，PPT共一百五十五頁，創(chuàng)作于2022年6月There are retroviruses which lac

46、k oncogenes but still can induce cancer. This is due to the fact that the virus has inserted its genetic material (in the form of DNA) very close to a normally occurring oncogene in the genetic material of the cell. This may result in an increased turn-over of the oncogene which may lead to abnormal

47、 cellular growth. The corresponding phenomenon can also occur in the absence of retroviruses. In this case there is a reorgani-zation of the genetic material in the cell. Such a reorganization may occur within a single chromosome or by exchange of material between chromosomes. Repeated copying of a

48、normal oncogene can lead to its amplification in the chromosome and consequently to increased amounts of the oncogene product. In certain brain tumors, glioblastomas, an amplified erbB-gene has been found, and a correspondingly increased neu-gene activity was shown in some forms of breast cancer. Th

49、e same effect can be seen when there is a reciprocal exchange of segments between chromosomes (translocation). Thus the normal myc-gene on chromosome 8 has been translocated to chromosome 14 in many patients with Burkitts lymphomas (Figure 3). The insertion of the myc-gene containing chromosome segm

50、ent is such that it becomes located close to hyperactive genes directing the synthesis of antibody protein. As a 第三十三張，PPT共一百五十五頁，創(chuàng)作于2022年6月consequence the myc-gene becomes activated. Chromosome translocations occur in many different tumors. Chromosome analysis can therefore be of considerable value

51、 for localization of genetic changes in the genome critical for tumor development. Figure 3. Chromosome translocation in Burkitts lymphoma. Segments have been exchanged between chromosomes 8 and 14 which has activated the oncogene myc. 第三十四張，PPT共一百五十五頁，創(chuàng)作于2022年6月Oncogenes with point mutations have b

52、een observed in many tumors. These mutations may cause alterations in the amino acid composition of the gene product. A well-known example of such a modification is the exchange of amino acid 12 from glycine to valine in the ras gene productwhich has been observed in human tumor material. The mutati

53、on may also be somewhat more extensive leading to the absence of part of the protein (deletion). Different examples of modified oncogenes in human tumor material are given in Table I. 第三十五張，PPT共一百五十五頁，創(chuàng)作于2022年6月The Importance of Viruses for Cancer in ManCancer is not a contagious disease. However, i

54、nfectious agents like viruses can contribute to the origin of cancer. Thus, it is by use of retroviruses that most oncogenes were identified, the starting materials in such investigations often being highly specialized, experimentally derived tumors. It seems likely that retroviruses play a relative

55、ly limited role for the development of cancer under natural conditions. The only known example in man in which a retrovirus infection contributes to the origin of cancer is the HTLV-1 associated lymphomas which occur in Japan. However, there are other kinds of viruses which can contribute to the dev

56、elop-ment of tumors in man. All these viruses have DNA as their genetic material. As examples can be mentioned papillome (wart) viruses and Epstein-Barr virus, a type of herpes virus. Certain types of papillome viruses play a role for the development of cervical cancer in the genital tract, while Ep

57、stein-Barr virus is an important factor for the development of Burkitts lymphomas in Africa and nasopharyngeal cancer in Asia. However, in all these cases factors in addition to the virus infections are required for the cancer to develop. 第三十六張，PPT共一百五十五頁，創(chuàng)作于2022年6月（二）病毒癌基因和對應(yīng)原癌基因的比較 原癌基因的限制性表達產(chǎn)物具有促

58、進細胞生長、增殖、分化和發(fā)育等生理功能，屬于正常的調(diào)節(jié)基因。細胞原癌基因外顯子序列在進化上極為保守，被稱為持家基因（house keeping gene），說明這類基因的表達產(chǎn)物在生命活動中是必需的。在受到某些化學(xué)、物理或生物性等因素作用下原癌基因因結(jié)構(gòu)、數(shù)量等改變而被激活后能使細胞發(fā)生惡性轉(zhuǎn)化。 第三十七張，PPT共一百五十五頁，創(chuàng)作于2022年6月 病毒癌基因和對應(yīng)原癌基因比較有序列的同源性和相似表達產(chǎn)物，但病毒癌基因經(jīng)過病毒自身改變修飾，和對應(yīng)的原癌基因比較，主要存在以下一些差別： 1、病毒癌基因無內(nèi)含子,而原癌基因通常有內(nèi)含子 或插入序列。2、病毒癌基因較原癌基因有較強的轉(zhuǎn)化細胞功能，

59、 其原因在于病毒癌基因與同源的原癌基因在外顯 子序列中存在著微小的差別。第三十八張，PPT共一百五十五頁，創(chuàng)作于2022年6月3、病毒癌基因常會出現(xiàn)堿基取代或堿基缺失等突變, 而原癌基因則較少發(fā)現(xiàn)這類突變。4、病毒癌基因通常丟失了原癌基因兩端的某些調(diào)控 序列，而在病毒高效啟動子作用下有較高的轉(zhuǎn)錄 活性。 第三十九張，PPT共一百五十五頁，創(chuàng)作于2022年6月（三）癌基因的分類 依據(jù)其基因結(jié)構(gòu)與功能特點可將大部分原癌基因歸于以下幾個家族:1、src家族: 包括src、abl、fes、fgr、fps、fym、kck 、lck、lyn、ros、tkl和yes 等基因。 Src 是最早被發(fā)現(xiàn)的癌基因。

60、其表達產(chǎn)物的氨基酸序列具有較高同源性和酪氨酸蛋白激酶活性以及同細胞膜結(jié)合的性質(zhì)，定位于胞膜內(nèi)側(cè)或跨膜分布。第四十張，PPT共一百五十五頁，創(chuàng)作于2022年6月2、ras家族: 包括3類密切相關(guān)的成員,即H-ras、K-ras及N-ras。雖其核苷酸序列的同源性較少，但編碼蛋白質(zhì)的分子量均為21 000,即p21。其表達產(chǎn)物多屬傳遞信號的小G蛋白，能結(jié)合GTP，有GTP酶活性，并參與細胞內(nèi)cAMP水平的調(diào)節(jié)。 3、myc家族: 包括c-myc、L-myc、N-myc、fos、ski等基因,其表達產(chǎn)物定位于細胞核內(nèi),為DNA結(jié)合蛋白類, 或為轉(zhuǎn)錄調(diào)控中的反式作用因子,有直接的調(diào)節(jié)其他基因轉(zhuǎn)錄的作用