(優(yōu)選)第二十章癌基因和抑癌基因課件

1、（優(yōu)選）第二十章癌基因和抑癌基因Measuring transformation in-vitroNormaltransformed 腫瘤是機(jī)體在各種致瘤因素的作用下，局部組織的細(xì)胞在基因水平上失掉了對(duì)其生長(zhǎng)的正常調(diào)控，導(dǎo)致異常增生而形成的新生物。 致瘤因素 正常細(xì)胞 基因改變 腫瘤細(xì)胞Development of CancerDefective cell cycles checkpoints mechanisms allows errors in the cell duplication process to persist into the next generation and can

2、lead to and regulated proliferation and the development of cancer.Two different types of mutations contribute to cancer formation: activating mutations in proto-oncogene and inactivating mutations in tumor suppressor genes.OncogenesStimulate ProliferationInhibit DifferentiationInhibit ApoptosisTumor

3、 Suppressor GenesInhibit ProliferationPromote DifferentiationStimulate Apoptosis一、癌基因的基本概念癌基因（oncogene）是指存在于正常細(xì)胞內(nèi)，與細(xì)胞生長(zhǎng)發(fā)育調(diào)控有關(guān)的一組結(jié)構(gòu)基因。癌基因發(fā)生結(jié)構(gòu)異?；虮磉_(dá)異常時(shí)，可以引起細(xì)胞癌變。癌基因可按其來(lái)源不同而分為病毒癌基因（v-onc）和細(xì)胞癌基因（c-onc）。 Oncogenes were first discovered in certain retroviruses and were later identified as cancer-causing ag

4、ents in many animals First link between viruses and cancer proposed by Francis Peyton Rous in 1910 (Nobel Prize, 1966): cell-free extracts from chicken tumors injected into healthy chickens caused new tumors.History of oncogeneRous Peyton ：The 1966 Nobel Prize in Physiology or Medicine雞肉瘤病毒基因組結(jié)構(gòu)圖 調(diào)節(jié)

5、和啟動(dòng)轉(zhuǎn)錄 LTR gag pol env src LTR 長(zhǎng)末端重復(fù)序列癌基因正常的病毒基因產(chǎn)生病毒核心蛋白產(chǎn)生逆轉(zhuǎn)錄酶和整合酶 產(chǎn)生病毒 外膜蛋白產(chǎn)生酪氨酸蛋白激酶Rous Sarcoma Virus (RSV)Discovered by Harold Varmus and Bishop, 1975-76 (Nobel Prize, 1989).A transforming retrovirus: a cancer-causing single-stranded RNA virus that uses reverse transcriptase enzyme to make ssDNA,

6、then ds DNA, which integrates into host DNA.Note: not all oncogenes caused by viruses.100s of oncogenes now known.Human T-cell leukemia virus (HTLV) is a human RV; codes a TF.Retroviral life cycleFigure 6 Retroviral life cycleRetroviruses have two identical copies of a plus single-stranded RNA genom

7、e and an outer envelope containing protruding viral glycoproteins. After envelope glycoproteins on a virion interact with a specific host-cell membraneprotein or group of proteins, the retroviral envelope fuses directly with the plasma membrane without first undergoing endocytosis (step 1). Followin

8、g fusion, the nucleocapsid enters the cytoplasm of the cell; then deoxynucleoside triphosphates from the cytosol enter the nucleocapsid, where viral reverse transcriptase and other proteins copy the ssRNA genome of the virus into a dsDNA copy (step 2). The viral DNA copy is transported into the nucl

9、eus (only one host-cell chromosome is depicted) and integrated into one of many possible sites in the host-cell chromosomal DNA (step 3). The integrated viral DNA, referred to as a provirus, is transcribed by the host-cell RNA polymerase, generating mRNAs (light red) and genomic RNA molecules (dark

10、red). The host-cell machinery translates the viral mRNAs into glycoproteins and nucleocapsid proteins (step 4). The latter assemble with genomic RNA to form progeny nucleocapsids, which interact with the membrane-bound viral glycoproteins,. Eventually the host-cell membrane buds out and progeny viri

11、ons are pinched off (step 5). Origin of Transforming Retroviruses病毒癌基因v-src來(lái)源于宿主細(xì)胞的C-SRC基因 逆轉(zhuǎn)錄復(fù)制整合轉(zhuǎn)錄感染病毒RNARNA-DNA前病毒DNA細(xì)胞基因組 DNA病毒RNA-癌基因RNA病毒顆粒宿主細(xì)胞再感染宿主細(xì)胞攜帶癌基因的病毒顆粒RNA病毒與宿主細(xì)胞基因組整合過(guò)程示意圖Proto-oncogenes癌變因此，病毒癌基因（v-onc）就是指一類存在于腫瘤病毒中，能使宿主細(xì)胞發(fā)生惡性轉(zhuǎn)化的基因。 病毒癌基因的特點(diǎn) 病毒癌基因無(wú)內(nèi)含子,而原癌基因通常有內(nèi)含子或插入序列。病毒癌基因較原癌基因有較強(qiáng)的轉(zhuǎn)

12、化細(xì)胞功能，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。病毒癌基因常會(huì)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。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(dòng)子作用下有較高的轉(zhuǎn)錄活性。二、細(xì)胞癌基因 細(xì)胞癌基因(c-onc)又稱為原癌基因（proto-oncogene），存在于細(xì)胞基因組中、正常情況下處于靜止或低水平（限制性）表達(dá)狀態(tài)，對(duì)維持細(xì)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(xì)胞惡變的基因。細(xì)胞癌基因的特點(diǎn)：廣泛存在于生物界基因序列高度保守表達(dá)產(chǎn)物對(duì)細(xì)胞正常生長(zhǎng)、繁殖、發(fā)育和分化起著精確的調(diào)控作用。基因結(jié)構(gòu)發(fā)生異?；虮?/p>

13、達(dá)失控，導(dǎo)致細(xì)胞生長(zhǎng)增殖和分化異常二、癌基因活化的4種機(jī)制示意圖 指來(lái)源于病毒等的啟動(dòng)子或增強(qiáng)子插入到細(xì)胞癌基因的附近或內(nèi)部而使其開(kāi)放并異常轉(zhuǎn)錄。如雞白細(xì)胞增生病毒引起的淋巴瘤，就是由于病毒的DNA序列整合到宿主細(xì)胞c-myc基因附近，成為該基因的強(qiáng)啟動(dòng)子，導(dǎo)致c-myc基因過(guò)強(qiáng)表達(dá)。（一）插入激活c-myc原癌基因的插入激活 即基因數(shù)量或拷貝數(shù)目明顯增加。常見(jiàn)的為myc原癌基因，由于其基因數(shù)目的增多而使其表達(dá)的蛋白產(chǎn)物增多。（二）基因擴(kuò)增 常見(jiàn)的為ras原癌基因的點(diǎn)突變。 ras原癌基因點(diǎn)突變后導(dǎo)致其GTPase活性下降，不能將其結(jié)合的GTP迅速水解，從而使其持續(xù)保持激活狀態(tài)。 正常細(xì)胞 H

14、-ras 基因堿基序列 ATG ACG GAA TAT AAG CTG GTG GTG GTG GGC GCC GGC GGT GTG腫瘤細(xì)胞 H-ras 基因堿基序列 ATG ACG GAA TAT AAG CTG GTG GTG GTG GGC GCC GTC GGT GTG正常細(xì)胞 P21 蛋白氨基酸序列 Met Thr Glu Tyr Lys Leu Val Val Val Gly Ala Gly Ala Val腫瘤細(xì)胞 P21 蛋白氨基酸序列 Met Thr Glu Tyr Lys Leu Val Val Val Gly Ala Val Ala ValH-ras基因的點(diǎn)突變 （三）點(diǎn)

15、突變Ras Proto-oncogeneMutated in 30% of all cancers.A “molecular switch” in the signal transduction pathway leading from growth factors to gene expression controlling cell proliferation: GF receptor Ras TF target genes growth.A single amino acid change in Ras protein can cause constant stimulation of

16、the pathway, even in the absence of growth factors.由于染色體重排而導(dǎo)致細(xì)胞癌基因從正常位置轉(zhuǎn)移到另一位置，常常是插入一啟動(dòng)子后而使其轉(zhuǎn)錄活性增加。Burkitt淋巴瘤中，含有c-myc的8號(hào)染色體易位，與14號(hào)染色體連接，靠近免疫球蛋白肽鏈的基因，與該區(qū)活性很高的啟動(dòng)子連接而受到活化。c-abl原癌基因，經(jīng)重排后插入到另一稱為bcr基因的啟動(dòng)子之后，而使其轉(zhuǎn)錄活性增加，從而引起慢性粒細(xì)胞性白血病的發(fā)生。 （四）染色體易位Chromosomal Translocation that creates Philadelphia Chromosome

17、BCR-ABL Oncogene: Breaks in ABL Gene of Chromosome 9 andBCR Gene of Chromosome 22Fusion Protein causes Chronic Myelogenous Leukemia出現(xiàn)新的表達(dá)產(chǎn)物 出現(xiàn)過(guò)量的正常表達(dá)產(chǎn)物出現(xiàn)異常、截短的表達(dá)產(chǎn)物 癌基因激活的結(jié)果：不同癌基因有不同的激活方式，一種癌基因也可有幾種激活方式： c-myc、ras腫瘤細(xì)胞中常發(fā)現(xiàn)兩種或多種細(xì)胞癌基因的活化，如白血病細(xì)胞株HL-60中有c-myc和N-ras的同時(shí)活化。例：原代培養(yǎng)大鼠胚胎成纖維細(xì)胞作用于細(xì)胞膜上的受體系統(tǒng)或直接被傳遞至細(xì)

18、胞內(nèi)，通過(guò)蛋白激酶活化轉(zhuǎn)錄因子，引發(fā)一系列基因的轉(zhuǎn)錄激活。三、原癌基因的產(chǎn)物與功能sis表達(dá)蛋白P28和PDGF一樣能促進(jìn)血管的生長(zhǎng)。（一）細(xì)胞外生長(zhǎng)因子 例如：（二）跨膜的生長(zhǎng)因子受體：接受細(xì)胞外的生長(zhǎng)信號(hào)并將其傳入胞內(nèi)。受體的胞質(zhì)結(jié)構(gòu)區(qū)具有特異的蛋白激酶活性，通過(guò)磷酸化作用使其結(jié)構(gòu)發(fā)生改變，增加激酶對(duì)底物的活性，促進(jìn)生長(zhǎng)信號(hào)在胞內(nèi)的傳遞。 例如 EGFR、HER2有酪氨酸特異的蛋白激酶活性。非受體酪氨酸激酶(src，abl)、絲氨酸/蘇氨酸激酶(raf)，ras蛋白(H-ras，K-ras和N-ras)及磷脂酶(crk產(chǎn)物)。（三）細(xì)胞內(nèi)信號(hào)傳導(dǎo)分子原癌基因的產(chǎn)物作為胞內(nèi)信息傳遞體系成員，

19、或者通過(guò)影響第二信使作用，將接受到的信號(hào)由胞內(nèi)傳至核內(nèi)，促進(jìn)細(xì)胞生長(zhǎng)。 例如：（四）核內(nèi)轉(zhuǎn)錄因子某些癌基因表達(dá)蛋白定位于細(xì)胞核內(nèi)，與靶基因的順式調(diào)控元件相結(jié)合直接調(diào)節(jié)靶基因的轉(zhuǎn)錄活性。 例如：c-fos是一種即刻早期反應(yīng)基因(immediate early gene，IEG)。作為傳遞信息的第三信使。 生長(zhǎng)因子 生長(zhǎng)因子受體 蛋白激酶及其他信號(hào)轉(zhuǎn)導(dǎo)組分 細(xì)胞周期蛋白 細(xì)胞凋亡調(diào)控因子 轉(zhuǎn)錄因子原癌基因BRAF所編碼的蛋白質(zhì)屬于絲/蘇氨酸激酶，是MAPK信號(hào)通路的重要組成分子，在調(diào)控細(xì)胞增殖、分化等方面發(fā)揮重要作用。四、癌基因表達(dá)產(chǎn)物促進(jìn)腫瘤發(fā)生發(fā)展約60%的黑素瘤中BRAF發(fā)生突變，其第600

20、位氨基酸從纈氨酸突變?yōu)楣劝彼幔╒600E）最為常見(jiàn)，導(dǎo)致B-Raf的持續(xù)激活。（一）BRAF 例如：分子靶向藥物 威羅菲尼VemurafenibHER2是表皮生長(zhǎng)因子受體家族成員，具有蛋白酪氨酸激酶活性，能激活下游信號(hào)通路，從而促進(jìn)細(xì)胞增殖和抑制細(xì)胞凋亡。在30%的乳腺癌中HER2基因發(fā)生擴(kuò)增或者過(guò)度表達(dá)，其表達(dá)水平與治療后復(fù)發(fā)率和不良預(yù)后顯著相關(guān)。（二）HER2例如：?jiǎn)慰寺】贵w藥物 赫塞汀Herceptin慢性粒細(xì)胞白血病患者的9號(hào)染色體與22號(hào)染色體之間發(fā)生易位，從而融合產(chǎn)生了癌基因BCR-ABL，編碼的蛋白質(zhì)Bcr-Abl具有持續(xù)活化的蛋白酪氨酸激酶活性，能促進(jìn)細(xì)胞增殖，并增加基因組的不

21、穩(wěn)定性。在95%的慢性粒細(xì)胞白血病患者中都伴隨有BCR-ABL融合基因的產(chǎn)生，在一些急性淋巴白血病患者中也有發(fā)現(xiàn)。（三）BCR-ABL 例如：分子靶向藥物 伊馬替尼 ImatinibAcquired mutations of oncogenes Most cancer causing mutations involving oncogenes are acquired, not inherited. They generally activate oncogenes by chromosome rearrangements, gene duplication, or mutation. For

22、 example, a chromosome rearrangement leads to formation of the gene called BCR-ABL. This leads to the disease chronic myeloid leukemia (CML). the gain-of-function mutations that convert proto-oncogenes to oncogenes act dominantly; that is, mutation in only one of the two alleles is sufficient for in

23、duction of cancer.Inherited mutations of oncogenes A few cancer syndromes are caused by inherited mutations of proto-oncogenes Multiple endocrine neoplasia type 2 (多發(fā)性內(nèi)分泌瘤) is caused by an inherited mutation in the gene called RET. Inherited mutations in the gene called KIT cause hereditary gastroin

24、testinal stromal tumors (胃腸道間質(zhì)瘤, GIST). Inherited mutations in the gene called MET cause hereditary papillary renal cancer（乳頭狀腎癌）. Cancers Usually Result from a Series of Mutations in a Single CellColon Cancer:MSH2和MLH1基因失活染色體：改 變： 基 因： 5q 突變或缺失 FAP、APC、MCC？12q 突變 K-ras18q 缺失 DCC17q 缺失和突變 p53正 常腸上皮高

25、增殖腸上皮早期腺瘤中期 腺瘤晚期 腺瘤腺癌轉(zhuǎn) 移 癌nm23突變DNA低甲基化其他基因的改變（如TGF-受體）Tumor Suppressor Genes Tumor Suppressor genes: are genes that act to inhibit cell proliferation and tumor development. If Tumor Suppressor Gene is Mutated Inactivated It will lead to cell transformation 腫瘤抑制基因(tumor suppressor gene) 腫瘤抑制基因的概念也稱抗

26、癌基因（anticancer gene）或抑癌基因，是調(diào)節(jié)細(xì)胞正常生長(zhǎng)和增殖的基因。當(dāng)這些基因不能表達(dá)，或者當(dāng)它們的產(chǎn)物失去活性時(shí)，細(xì)胞就會(huì)異常生長(zhǎng)和增殖，最終導(dǎo)致細(xì)胞癌變。反之，若導(dǎo)入或激活它則可抑制細(xì)胞的惡性表型。Discovery of Tumor SuppressorsFirst discovered in 1960s by Henry Harris. Harris fused tumor cells with normal cells and discovered some of the hybrid cells were normal. Harris hypothesized th

27、at the normal cells contained gene products that suppressed uncontrolled cell proliferation.Five broad classes of proteins encoded by tumor-suppressor genesIntracellular proteins, such as the p16 cyclin-kinase inhibitor, that regulate or inhibit progression through a specific stage of the cell cycle

28、.Receptors for secreted hormones (e.g., tumor derived growth factor ) that function to inhibit cell proliferation.Checkpoint-control proteins that arrest the cell cycle if DNA is damaged or chromosomes are abnormal.Proteins that promote apoptosis.Enzymes that participate in DNA repair.Familial cance

29、r - RbSporadic retinoblastoma 60% of retinoblastoma cases. Develops in children with no family history. Occurs in one eye. Hereditary retinoblastoma 40% of retinoblastoma cases. Onset typically is earlier than sporadic cases. Multiple tumors involving both eyes.Retinoblastoma (Rb) caused bymutated R

30、b geneThe First Tumor-Suppressor Gene 視網(wǎng)膜母細(xì)胞瘤Alfred Knudsons 2-hit modelTwo mutations are required for the development of retinoblastoma. Sporadic retinoblastoma Child starts with two wild type alleles (RB+/RB+). Both alleles must mutate to produce the disease (RB/RB). Probability of both mutations

31、occurring in the same cell is low; only one tumor forms (e.g., one eye). Hereditary retinoblastoma Child starts with heterozygous alleles (RB/RB+). Only one mutation is required to produce disease (RB/RB). Mutations resulting in loss of heterozygosity (LOH) are more probable in rapidly dividing cell

32、s, and multiple tumors occur (e.g., both eyes).Loss of heterozygosity (LOH)雜合性缺失Rb基因的表達(dá)產(chǎn)物為P105Rb，在細(xì)胞內(nèi)存在低磷酸化型（活性型）和高磷酸化型（非活性型）兩種類型。不同類型的P105Rb對(duì)轉(zhuǎn)錄因子E2F有不同的親和力。Rb 基因的作用機(jī)制G0 G1期Rb蛋白E-2FS期E-2FDNAmRNADNAPRb蛋白Tumor Suppressors are Recessive Tumor suppressors must be inactivated This means both copies must

33、be lost/mutatedTumor suppressors and familial cancerHereditary cancer is caused by the inheritance ofone copy of a defective tumor suppressor1. Antagonize the action of oncogenes eg. p53 is activated by oncogenes. p53 protects against cancer by inducing cell cycle arrest and/or apoptosisFunctions of

34、 Tumor Suppressor genesmyccell growthp532. Block proliferation: Cell cycle inhibitors: eg. Rb blocks entry into S phase by binding to and inhibiting RB. INK-4 gene: that produces P16 that inhibits cdk4/cyclin D action ( to phosphorylate Rb gene to inactivate its action) Repressor transcription facto

35、rs: e.g.; WT1 is a repressor that appears to suppress transcription factor ( Insulin like growth factor) which will contribute in the development of tumor. Activator transcription factors: e.g.; SMAD family that are activated by TGF-, leading to inhibition of cell proliferation . P53: that produces

36、P21 that has the same action of P16 in inhibiting the action of cdk/cyclin. Functions of Tumor Suppressor genesPTEN通過(guò)阻斷PI3K/AKT信號(hào)通路抑制細(xì)胞的生長(zhǎng) 3. Induce apoptosis: Form of cell suicide. A cell which has lost growth control will often undergo apoptosis. Cell damage or stress can also lead to apoptosis. p

37、53 is a critical regulator of apoptosis. Transcription factor which activates pro-apoptotic moleculesFunctions of Tumor Suppressor genes Most commonly mutated gene in cancers (50% of total). When p53 is mutated, DNA-damaged cells are not arrested in G1 and DNA repair does not take place. This failur

38、e to arrest DNA-damaged cells will be repeated in subsequent cell cycles permitting other mutations to accumulate, culminating in neoplastic transformation. tumor formation and cancer.p53 Mutationsp53的結(jié)構(gòu)及其在清除DNA損傷細(xì)胞中的作用 p53 the guardian ofthe genomeRegulation of the cell cycle4. DNA Repair DNA repai

39、r prevents the accumulation of mutations Defects in DNA repair genes leads to genomic instability Accelerates the activation of oncogenes and the loss of tumor suppressors Many cancer prone syndromes associated with defects in DNA repair, BRCA1, ATM, MRE11, NBS,Functions of Tumor Suppressor genes A

40、small proportion of breast cancer is heritable. Two genes are associated with predisposition to breast cancer. BRCA1 on chromosome 17 BRCA2 on chromosome 13 Normal function of both is in repair of ds DNA breaks.Breast Cancer Tumor SuppressorsTumor suppressor genes- summaryTumor suppressor genes inhi

41、bit oncogenes suppress proliferation Induce cell death repair DNA prevent mutation These are “l(fā)oss of function” or recessive mutations. Responsible for hereditary forms of cancer Being heterozygous enhances the probability of cancer but this will require a mutation in the corresponding other allele.

42、 e.g., it need to be homozygous for the gene.Tumor suppressor genes- summaryp53 A transcription factor that regulates genes controlling cell division and cell death. Important in the cellular response to DNA damage. Aids in decision between repair and induction of cell death.Rb Functions by altering

43、 transcription factor activity. Contributes to the control of cellular division by acting as an inhibitor.APC The APC protein binds and stimulates the degradation of a transcription factor. Absence of functional APC protein leads to increased cell division.BRCA BRCA proteins have multiple functions

44、including repairing DNA damage and regulation of gene expression. Non-functional BRCA leads to compromised DNA repair and gene regulation.促進(jìn)正常細(xì)胞向腫瘤細(xì)胞轉(zhuǎn)化的因素 生長(zhǎng)因子Growth factors 第三節(jié) 生長(zhǎng)因子(growth factor)一類由細(xì)胞分泌的、類似于激素的信號(hào)分子，多數(shù)為肽類（含蛋白類）物質(zhì)，具有調(diào)節(jié)細(xì)胞生長(zhǎng)與分化的作用。內(nèi)分泌 (endocrine)旁分泌 (paracrine)自分泌 (autocrine) 作用模式 ： 生

45、長(zhǎng)因子分泌后，通過(guò)血液運(yùn)輸作用于遠(yuǎn)端靶細(xì)胞細(xì)胞分泌生長(zhǎng)因子作用于鄰近其它類型細(xì)胞，對(duì)自身細(xì)胞不發(fā)生作用生長(zhǎng)因子作用于合成及分泌該生長(zhǎng)因子的細(xì)胞本身一、生長(zhǎng)因子的分類和功能（一）生長(zhǎng)因子的分類生長(zhǎng)因子名稱組織來(lái)源功能表皮生長(zhǎng)因子（EGF）唾液腺、巨噬細(xì)胞、血小板等促進(jìn)表皮與上皮細(xì)胞的生長(zhǎng)，尤其是消化道上皮細(xì)胞的增殖肝細(xì)胞生長(zhǎng)因子（HGF）間質(zhì)細(xì)胞促進(jìn)細(xì)胞分化和細(xì)胞遷移促紅細(xì)胞生成素（EPO）腎調(diào)節(jié)成紅細(xì)胞的發(fā)育類胰島素生長(zhǎng)因子（IGF）血清促進(jìn)硫酸鹽參入到軟骨組織促進(jìn)軟骨細(xì)胞的分裂、對(duì)多種組織細(xì)胞起胰島素樣作用神經(jīng)生長(zhǎng)因子（NGF）頜下腺含量高營(yíng)養(yǎng)交感和某些感覺(jué)神經(jīng)元、防止神經(jīng)元退化血小板源生長(zhǎng)

46、因子（PDGF）血小板、平滑肌細(xì)胞促進(jìn)間質(zhì)及膠質(zhì)細(xì)胞的生長(zhǎng)、促進(jìn)血管生成轉(zhuǎn)化生長(zhǎng)因子（TGF-）腫瘤細(xì)胞、巨噬細(xì)胞、神經(jīng)細(xì)胞作用類似于EGF，促進(jìn)細(xì)胞惡性轉(zhuǎn)化轉(zhuǎn)化生長(zhǎng)因子（TGF-）腎、血小板對(duì)某些細(xì)胞起促進(jìn)和抑制雙向作用血管內(nèi)皮生長(zhǎng)因子（VEGF）低氧應(yīng)激細(xì)胞促進(jìn)血管內(nèi)皮增殖和新生血管分化（二）生長(zhǎng)因子的功能生長(zhǎng)因子的生物學(xué)效應(yīng)主要表現(xiàn)在促進(jìn)細(xì)胞生長(zhǎng)、分化、促進(jìn)個(gè)體發(fā)育等方面。但是有些生長(zhǎng)因子具有雙重調(diào)節(jié)作用或負(fù)調(diào)節(jié)作用。 同一生長(zhǎng)因子對(duì)不同細(xì)胞的作用有所不同 一種細(xì)胞也可受不同生長(zhǎng)因子調(diào)節(jié) 具有負(fù)調(diào)節(jié)作用的生長(zhǎng)因子比較少，人們通常把這種負(fù)調(diào)節(jié)因子（negative growth facto

47、r）稱為細(xì)胞生長(zhǎng)抑制因子。 產(chǎn)生相應(yīng)第二信使胞內(nèi)相關(guān)蛋白質(zhì)被磷酸化與膜受體結(jié)合酪氨酸激酶活化蛋白激酶活化 核內(nèi)轉(zhuǎn)錄因子活化基因轉(zhuǎn)錄與胞內(nèi)受體結(jié)合生長(zhǎng)因子 - 受體復(fù)合物，活化相關(guān)基因二、生長(zhǎng)因子作用機(jī)制The seven types of proteins that participate in controlling cell growthgrowth factors (I) growth factor receptors (II) signal-transduction proteins (III)transcription factors (IV) pro- or anti-apoptotic proteins (V)cell cycle control proteins (VI)DNA repair proteins (VII)Class VII mutations greatly increase t