oncogene,tumorsuppressorgene,growthfactor

1、Oncogenes, tumor-suppressor genes and growth factorsCell proliferation, differentiation and apoptosis play important roles in life processes. Theyare affected and regulated by many factors, including cancer genes and growth factors. If they are not normally regulated or controlled, cancers and other

2、 diseases may occur.Cancer is fundamentally a disease of regulation failure of tissue growth by alterations in oncogenes, tumor-suppressor genes and microRNA genes. The alterations are usually somatic events, although germ-line mutations can predispose a person to heritable or familial cancer.Oncoge

3、nesare genes potential to cause cancer by promoting cell growth and reproduction. Tumor suppressor genes are genes experimentally potential to“brake” cell malignancy deepening by inhibiting cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the i

4、nappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, sequential alterations in many genesare required to transform a normal cell into a cancer cell. So it is important to keep the idea in your mind that the occurrence and dev

5、elopment of cancer is a complicated procedures of multi-steps involving multi-genes and multi-factors, such as chemicals, physical agents, viruses, hormones, growth factors and others.1 Oncogenes1.1 Definition of viral oncogene, cellular oncogene and proto-oncogeneOncogenes are genes that have the p

6、otential to cause cancer, they are classified into two categories by source, one is viral oncogenes (v-onc) which are the regions in the viral genome (DNA in DNA tumor-viruses or RNA in RNA-tumor viruses) that can be carried into a cell by the virus and cause the host cell to take on new properties

7、such as immortalization and anchorage-independent growth. The other is the cellular oncogenes (c-onc) existing in the cell genome and most of them have viral counterparts. When not mutated or activated, cellular oncogenesare also specially designated as proto-oncogenes which are evolutionary highly

8、conserved genes required for normal cell functions including proliferation and differentiation and so they are indispensable to normal human development and the maintenance of tissues and organs. When over-expressed in the absolute number of proto-oncogene products or activated at inappropriate time

9、s or mutated to acquire the new properties, we say proto-oncogenes are converted to oncogenes or cellular oncogenes which can induce transformation. So cellular oncogenes refer to proto-oncogenes or activated proto-oncogenes or both in different cases, when refer to activated proto-oncogenes, it is

10、of the same meaning of oncogenes or activated oncogenes.There are two ways to understand that most of cellular oncogenes (proto-oncogenes) have the viral counterparts. First, it means the sequences of proto-oncogenes are similar but not identical to the viral counterparts: (1) There areintrons in pr

11、oto-on coge nes but not in viral on coge nes. (2) Ofte n there are mutati ons or sequenee losses or inserted sequencesin the viral oncogenes comparing with the proto-on coge nes, so the viral on coge ne is fun dame ntally activated or high expressed in cell and of transforming ability. Second, some

12、cellular oncogenes do not have the viral coun terparts and vice versa. To deepe n un dersta nding of the senten ce, we shall briefly talk about viruses and can cers n ext.1.2 Viruses and cancerTumor cells also can arise by non-gen etic means through the acti ons of specific tumor viruses.There are t

13、wo classesof tumor viruses , DNA tumor viruses and RNA tumor viruses, the latter also being referred to as retroviruses for containing reverse tran scriptase. RNA tumor viruses are com mon in chicke ns, mice and cats but rare in humans. The only currently known human retroviruses are the human T-cel

14、l leukemia viruses (HTLVs) and the related retrovirus, huma n immuno deficie ncy virus (HIV).Tablr 2:aswiaLcd wilh tuinao axmvmuDNA viiMS垃inpboi 皿華1泅血cancertlqialilh BLiver tEiircT卩埠jillcUUJ ilTJiBenign Yvarts. CL*niL raiKtiTUNA vimswifuwui 聞 Midenq win 罔Hiiimi T阳 LkuMii 田Kpcj ontV-fiI Cell HannI1TL

15、V-1Ifein cell laionftHTLVJAccord ing to the tran sformi ng speed of cells, RNA tumor viruses are classified into two groups, they are chronically transforming viruses which do not contain viral on coge ne and acutely tran sform ing viruses which contain viral on coge ne, for example, RSV contains an

16、 extra genev-src which is homologous to c-src but not vital to itself.In acutely transforming viruses of RNA tumor viruses, most of the viral on coge nes are origi nated from cellular genes by recomb in ati on betwee n a pare nt non-tra nsformi ng virus and host cellular DNA, which mea ns the cellul

17、ar on coge nes have been taken up into the genomes of retroviruses in the cause of evolution. But it is to be no ted that a few viral on coge nes of acutely tran sform ing RNA viruses are not originated from cellular genesand neither are the viral oncogenesof DNA tumor viruses.There are two ways for

18、 a virus to cause cancer: It may carry oncogenes into a cell or it may activate a cellular proto-oncogene when it infects the host.For DNA tumor viruses to cause can cer, ofte n they carry on coge nes into cells. In most cases, the mechanism of cellular transformation by DNA tumor viruses is the res

19、ult of protein-protein interaction between the viral oncogene protein and the cell prote ins of various functions in clud ing tumor repressor prote ins. Prote ins en coded by the DNA tumor viruses, termed tumor an tige ns or T an tige ns, can in teract with cellular proteins. This interaction effect

20、ively sequesters the cellular proteins (predominantly the tumor suppressor type) away from their normal functional locati ons within the cell and in activate the no rmal functions of the cellular protei ns. The E6 of HPV and the HBx an tigen of HBV can in teract with P53 to in hibit the tumor suppre

21、ssing function. Moreover, The E7 of HPV can interact with Rb and counteract the function of negative regulation of cell growth.For RNA tumor viruses to cause cancer,surely you are curious about how the chronically transforming viruses induce cancers as they do not have an oncogene. The reason is tha

22、t there are LTRs in the viral genome which contain promotors/enhancers of strong capability to enhance transcription, when the viral genome is inserted adjacent to cellular oncogenes such as c-myc by chance, the cellular oncogenes come under the LTR influence and thus is over expressed to increase t

23、he cell growth and block the cell differenciation. This is called oncogenesis by promotor/enhancers insertion. As to acutely transforming RNA viruses which contain viral oncogenes, there are two mechanisms causing cancer: one is by promotor/enhancers insertion as the the chronically transforming RNA

24、 viruses do to activate cellular oncogenes; the other is to carry viral oncogenesin the LTR context into cells and results in over expression of the oncogene proteins which are of the roles of growth factors, hormone receptors, G-proteins, and transcription factors as their cellular homologues do. T

25、herefore we shall discuss the products and functions of viral oncogenes of acutely transforming RNA viruses together with that of proto-oncogenes or cellular oncogenes in the coming text.1.3 proto-oncogenesAlthough we now know most of the viral oncogenes are originated from cellular genes by recombi

26、nation between a parent non-transforming virus and host cellular DNA in the cause of evolution, the oncogenes were first identified in oncogenic retroviruses, then evidences showed there were counterparts in the genome of cell. Now more than 40 viral oncogenes have been identified in acutely transfo

27、rming viruses of RNA tumor viruses and approximately 100 cellular oncogenes have been discovered. Proto-oncogenes are coined to term the normal forms of cellular oncogenes which are expressed under strict control in cell.Proto-oncogenesare evolutionary highly conserved genes existing in diverse spec

28、ies from yeast to human and they are indispensable to maintain normal physiological functions for their regulation of cell proliferation and differentiation. That is, They are normal genes rather than cancer genes in cells. However, when proto-oncogenes are mutated or high expressed atinappropriate

29、times or cells, they have the oncogenic potential by promoting cell reproduction, decreasing cell differentiation and inhibiting cell death. That is, when they are activated to be of oncogenic ability, we say they have been converted into oncogenes or cancer genes.1.3.1 Classification of proto-oncog

30、enesor viral oncogenes or cellular oncogenes(1) sis family: Its members encode growth factors. sis and int-2 are its members encoding platelet-derived growth factor B (PDGF-B) and fibroblast growth factor-2 (FGF-2) respectively.(2) erb family: Its members encode growth factor receptors.erb-1, erb-2，

31、fms， kit ， ros， mas are its members encoding epidermal growth factor receptor 1, epidermal growth factor receptor 2, colony stimulator factor 1, stem cell factor, an insulin receptor, an angiotensin receptors respectively.(3) src family: Its members encode non-receptor tyrosine kinases associating w

32、ith the cytoplasmic face of the plasma membrane. src, abl, yes, fes, fgr, lyn are its members.(4) ras family: Its members encode guanosine-triphosphate(GTP)-binding proteins. H-ras, K-ras, N-ras are its members.(5) raf family: Its members encode serine/threonine-specific protein kinases. Raf, mos, c

33、rk, pimare its members.(6) myc family: Its members encode transcription factor. myc, myb, fos, jun, erb-A are its members.1.3.2 Functions and products of proto-oncogenesor viral oncogenesor cellular oncogenes(1) Growth factorsThe sis gene encodes the PDGF B chain. The v-sis gene was the first oncoge

34、ne to be identified as having homology to a known cellular gene.The int-2 gene encodes an FGF-related growth factor.The kgf gene also encodesan FGF-related growth factor and was identified in gastric carcinoma and Kaposis sarcoma cells.(2) Receptor tyrosine kinasesGrowth factor receptors are of seve

35、ral different types dependent upon whether or not they exhibit intrinsic enzymatic activity upon growth factor binding and what type of intrinsic activity is associated with the receptor. Numerous growth factor receptors exhibit intrinsic tyrosine kinase activity and many receptors in this class hav

36、e been shown to have oncogenic potential.The fims gene encodes the colony stimulating factor-1 receptor and was first identified as a retroviral oncogene. Theflg , homology to the fms gene, encodes a form of the fibroblast growth factor (FGF) receptor.The neu gene amplified in numerous cancers was i

37、dentified as an EGF receptor-related gene in an ethylnitrosourea-induced neuroblastoma.The trk gene encodes the NGF receptor-like proteins. It was first found in pancreatic cancer.The met proto-oncogene encodes the hepatocyte growth factor (HGF)/scatter factor (SF) receptor.The kit gene which encode

38、s the receptor for stem cell factor (SCF) is found constitutively activated in sarcomas.(3) Membrane associated non-receptor tyrosine kinasesThe src gene was the first identified oncogene and SRC is the archetypal protein tyrosine kinase.The lck gene was isolated from a T cell tumor line and has bee

39、n shown to be associated with the CD4 and CD8 antigens of T cells.The chromosome (chromosome 9) containing the abl proto-oncogene is frequently rearranged in chronic myelogenous leukemias (CMLs). The majority of rearrangementsinvolve a reciprocal translocation between the chromosome 9 and chromosome

40、 22 near a locus termed the break-point cluster region (BCR). The result is a constitutively active ABL tyrosine kinase domain fused to the BCR coding region forming what is referred to as the BCR-ABL fusion protein.(4) G-protein coupled receptorsThe mas gene was identified in a mammary carcinoma an

41、d has been shown to be the angiotensin receptor.(5) Membrane associated G-proteinsThere are numerous proteins in the cell whose function is regulated by the binding and hydrolyzing of GTP. These proteins all belong to a class of protein called G-proteins. In addition to the G-proteins themselves, th

42、eir activity is regulated by associatedGTPase-activating (GAP) proteins (sometimes called guanine nucleotide exchange factors, GEFs).There are three different homologs of theras gene, each of which was identified in a different type of tumor cell. The ras gene is one of the most frequently disrupted

43、 genes in colorectal carcinomas. The three ras genes are identified as K- ras, N- ras and H- ras.Two G-protein regulators that have been identified as oncogenes ardebl and vav. dbl is involved in the exchange of GTP for GDP in several proteins of the small G-protein class. These includerho, rac, and

44、 cdc42. The VAV protein is thought to be an exchange factor for RAS (thus a RAS-GAP) although it also contains zinc-finger domains characteristic of transcription factors.(6) Serine/threonine kinasesThe raf gene is involved in the signaling pathway of most RTKs. It is likely responsible for threonin

45、e phosphorylation of MAP kinase following receptor activation.The mos gene (originally identified in the Moloney murine sarcome virus) is normally expressed in germ cells and functions during oocyte maturation.(7) Nuclear DNA-binding/transcription factorsMany genes that are altered resulting in canc

46、er encode proteins that are transcription factors. It would seem obvious that a genetic alteration that disrupts the normal expression and regulation of a transcription factor could have profound implications for cellular regulation.The myc gene was originally identified in the avian myelocytomatosi

47、s virus. A disrupted human myc gene has been found to be involved in numerous hematopoietic neoplasias. Disruption of myc has been shown to be the result of retroviral integration and transduction as well as chromosomal rearrangements. There are threme yc genes, each of which has been shown to be in

48、volved in cancerm: yc, N- myc, and L- myc.The fos gene was identified in the feline osteosarcoma virus. The protein interacts with a second proto-oncogenic protein, JUN to form a transcriptional regulatory complex.The p53 gene was originally identified as a major nuclear antigen in transformed cells

49、. The p53 gene is the single most identified mutant protein in human tumors.Mutant forms of the p53 protein interfere with cell growth suppressor effects of wild-type P53 indicating that the p53 gene product is actually a tumor suppressor.(8) Apoptosis regulatorsMany tumors overexpress BCL2 or relat

50、ed proteins. The BCL2 gene, which is involved in the initiation of almost all follicular lymphomas and some diffuse large B-cell lymphomas, encodes a cytoplasmic protein that localizes to mitochondria and increases cell survival by inhibiting apoptosis. BCL2 is also important in chronic lymphocytic

51、leukemia and lung cancer. The BCL2 family members BCL-XL and BCL2 inhibit apoptosis and are up-regulated in many cancers. Two main pathways lead to apoptosis: the stress pathway and the death-receptor pathway. The stress pathway is triggered by proteins that contain the BCL2 homology 3 domain; this

52、domain inactivates BCL2 and BCL-XL (which normally inhibit apoptosis) and thereby activates the caspasesthat induce apoptosis. The death-receptor pathway is activated by the binding of Fas ligand, TRAIL, and tumor necrosis factor to their corresponding (death) receptors on the cell surface. Activati

53、on of death receptors activates caspases that cause cell death(9) Cell cycle regulatorsThe growth of human cells, involving DNA replication and cell division in the cell cycle, is activated by growth factors, hormones, and other messengers.These activators work through cyclins and cyclin- dependent

54、kinases (CDKs) that control progression from one phase of the cycle to another. For quiescent cells to proliferate, they must leave G0 and enter the G1 phase of the cell cycle. If the proper sequence of events occurs during G1, the cells enter the S phase and are committed to DNA replication and cel

55、l division. Similarly, during G2 cells make a commitment to mitotic division. CDKs are made constantly throughout the cell cycle but require binding of a specific cyclin to be active. Different cyclins made at different times in the cell cycle control each of the tran sitio ns (G1/S, S/G2, G2/M). Th

56、e activity of the cycl in -CDK complex is further regulated through phosphorylation and through inhibitory proteins called cyclin-dependent kinase inhibitors (CKIs). CKIs slow cell cycle progression by bi ndi ng and in hibit ing the CDK yclin complexes. CDKs are also con trolled through activating p

57、hosphorylation by CAK (cyclin-activating kinases) and inhibitory hyperphosphorylation kinases. To illustrate the role of these proteins, consider some of the events occurring at the G1/S checkpoint. Because the cell is committed to DNA replication and division once it enters the S phase, multiple re

58、gulatory proteins are involved in determining whether the cell is ready to pass this checkpoint. These regulatory proteins include cdk4 and cdk6 (which are constitutively produced throughout the cell cycle), cyclin D (whose synthesis is only induced after growth factor stimulation of a quiescent cel

59、l), the retinoblastoma gene product (Rb), and a class of transcription factors known collectively as E2F. In quiescent cells, Rb is complexed with E2F, resulting in inhibition of these transcription factors. On growth factor stimulation, the cyclin Ds are induced (there are three types of cyclin D; D1, D2, and D3). They bind to cdk4 and cdk6, converting them to active protein kinases. One of the targets of cyclin/cdk phosphorylati