肿瘤分子生物学
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The ras oncogenes were the first nonviral oncogenes to be recognized. One
mutation which changes ras from a proto-oncogene to an oncogene eliminates its GTPase activity so that, even with a functional, GAP protein, ras will not hydrolyze GTP-GDP and remains active, coupling to the MAP kinase cascade and triggering the expression of early response genes Jun and Fos.
Vinculin(纽带蛋白), a protein that helps link the cytoskeleton to the cell
membrane shows elevated phosphorylation in transformed cells and may be involved in the morphological changes observed in transformed cells.
are normal cellular genes which promote normal growth and development
细胞癌基因的分类
生长因子类(growth factor )—sis 生长因子受体类(growth factor receptors)—PDGF、
EGF、 酪氨酸激酶类(tyrosine protein kinase—Src
Malignant Tumor
atypical of tissue of origin Slow or rapid rate of growth Usually progressive; Fatal if untreated Growth by infiltration or metastasis Tissue destruction is common Recurrence is common Fatal prognosis if uncontrolled
the unregulated proliferation of cells；
Benign Tumor
typical of tissue of origin Slow rate of growth Slowly progressive; Not fatal if untreated Encapsulated growth No tissue destruction Rare recurrence Poor prognosis only if unable to remove
Oncogenes may cause mutant receptor proteins
mutant receptor delivers continuous mitogenic signals even in absence of growth factors
Over-expression of receptors
G-proteins: both trimeric and monomeric
for example, a mutation in Gs can make it an oncogene by eliminating the GTPase activity, thus causing it to signal perpetually. In epithelial cells this can lead to symptoms of cholera (discussed previously) but can also lead to uncontrolled growth for cell types in which cAMP levels are linked to transcription of immediate early genes/early response genes (pituitary cells leading pituitary tumors).
生长不受控制； 威胁生命 难以治愈
Definition of cancer---by laboratory workers
Cancer is a disorder that occurs at a cellular level Cancer occurs when genetic alterations result in
This triggers an allosteric change in Gα causing
GDP to leave and be replaced by GTP.
GTP activates Gα causing it to dissociate from GβGγ (which remain linked as a dimer).
癌基因的发现
1911 Rous发现有肉瘤病毒的鸡肉瘤无细 胞注射液注入鸡体内可诱发新的肿瘤；
鸡Rous肉瘤病毒核酸中有一个特殊片段src
可使细胞转化； 正常细胞中的原癌基因与病毒中的癌基因
是同源的。
RNA 病毒致癌的途径
提供癌基因； 插入改变宿主基因活性的病毒序列。
DNA 病毒致癌的途径
1. used to treat metastatic BC
mutations might constituitively activate these proteins
tyrosine protein kinase—Src
产物有使酪氨酸磷酸化的蛋白激酶活性， 定位与胞膜内面或跨膜分布
Intracellular Signal Transducers
more common
c-erb B-2 (Her-2 或 c-neu)
a mutant version of EGF receptor that is amplified 15-30% in breast cancers and other adenocarcinomas
Herceptin—drug that blocks receptor, inhibits growth
传导蛋白（Signal transducing proteins）： Ras（p21)
核内蛋白类( trascription factors) 细胞周期蛋白
与细胞凋亡相关的因子：bcl-2（related to
apoptosis)
Growth factors
Sis: protooncogene for PDGF
tumor suppressor gene:
Genes that normally restrain cell growth but, when missing or inactivated by mutation, allow cells to grow uncontrolled.
Oncogenes
viral oncogene
A gene in the viral genome that contributes to malignancies in vertebrate hosts
proto-oncogenes (cellular-oncogene):
are normal cellular genes which promote normal growth and development
Oncogene and tumor suppressor gene
Oncogene:
also called cancer-promoting genes or transforming genes. A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens.
Activated Gα in turn activates an effector molecule. In a common example (shown here), the effector molecule is adenylyl cyclase - an enzyme in the inner face of the plasma membrane which catalyzes the conversion of ATP into the "second messenger" cyclic AMP (cAMP)
直接通过它们的
2
v-onc 结合到宿
主蛋白，并使后
者失活而发挥作
用。
Oncogenes
viral oncogene
A gene in the viral genome that contributes to malignancies in vertebrate hosts
proto-oncogenes (cellular-oncogene)
several tumors have receptors for PDGF resulting in AUTOC、IGF-1，2、TGF
Growth factor receptors
Including : PDGF、EGF、IGF-1，2、TGF, et al.
转化细胞的特征
decreased growth factor requirements loss of capacity for growth arrest - transformed
cells will continue to divide even when nutrients are limited (immortalization) loss of dependence on anchorage for growth can form colonies when suspended as single cells in agar changed cell morphology loss of contact inhibition
In the inactive state, Gα has GDP in its binding site.
When a hormone or other ligand binds to the associated GPCR, an allosteric change takes place in the receptor (that is, its tertiary structure changes).
肿瘤分子生物学 The molecular basis of
cancer
Jingbo Xiong, Ph. D.
Definition of cancer---by clinical workers
临床定义：是一类以生长不受控制、侵入 周围组织并向身体其它部位转移为特征的 疾病的总称；
三个特征：
Signal transducing proteins---Ras
Cause of cancer
Environmental agents
chemicals radiation viruses
Inherited
Genetic basis
tumor is clonal expansion of single progenitor cell that has genetic damage
mutation which changes ras from a proto-oncogene to an oncogene eliminates its GTPase activity so that, even with a functional, GAP protein, ras will not hydrolyze GTP-GDP and remains active, coupling to the MAP kinase cascade and triggering the expression of early response genes Jun and Fos.
Vinculin(纽带蛋白), a protein that helps link the cytoskeleton to the cell
membrane shows elevated phosphorylation in transformed cells and may be involved in the morphological changes observed in transformed cells.
are normal cellular genes which promote normal growth and development
细胞癌基因的分类
生长因子类(growth factor )—sis 生长因子受体类(growth factor receptors)—PDGF、
EGF、 酪氨酸激酶类(tyrosine protein kinase—Src
Malignant Tumor
atypical of tissue of origin Slow or rapid rate of growth Usually progressive; Fatal if untreated Growth by infiltration or metastasis Tissue destruction is common Recurrence is common Fatal prognosis if uncontrolled
the unregulated proliferation of cells；
Benign Tumor
typical of tissue of origin Slow rate of growth Slowly progressive; Not fatal if untreated Encapsulated growth No tissue destruction Rare recurrence Poor prognosis only if unable to remove
Oncogenes may cause mutant receptor proteins
mutant receptor delivers continuous mitogenic signals even in absence of growth factors
Over-expression of receptors
G-proteins: both trimeric and monomeric
for example, a mutation in Gs can make it an oncogene by eliminating the GTPase activity, thus causing it to signal perpetually. In epithelial cells this can lead to symptoms of cholera (discussed previously) but can also lead to uncontrolled growth for cell types in which cAMP levels are linked to transcription of immediate early genes/early response genes (pituitary cells leading pituitary tumors).
生长不受控制； 威胁生命 难以治愈
Definition of cancer---by laboratory workers
Cancer is a disorder that occurs at a cellular level Cancer occurs when genetic alterations result in
This triggers an allosteric change in Gα causing
GDP to leave and be replaced by GTP.
GTP activates Gα causing it to dissociate from GβGγ (which remain linked as a dimer).
癌基因的发现
1911 Rous发现有肉瘤病毒的鸡肉瘤无细 胞注射液注入鸡体内可诱发新的肿瘤；
鸡Rous肉瘤病毒核酸中有一个特殊片段src
可使细胞转化； 正常细胞中的原癌基因与病毒中的癌基因
是同源的。
RNA 病毒致癌的途径
提供癌基因； 插入改变宿主基因活性的病毒序列。
DNA 病毒致癌的途径
1. used to treat metastatic BC
mutations might constituitively activate these proteins
tyrosine protein kinase—Src
产物有使酪氨酸磷酸化的蛋白激酶活性， 定位与胞膜内面或跨膜分布
Intracellular Signal Transducers
more common
c-erb B-2 (Her-2 或 c-neu)
a mutant version of EGF receptor that is amplified 15-30% in breast cancers and other adenocarcinomas
Herceptin—drug that blocks receptor, inhibits growth
传导蛋白（Signal transducing proteins）： Ras（p21)
核内蛋白类( trascription factors) 细胞周期蛋白
与细胞凋亡相关的因子：bcl-2（related to
apoptosis)
Growth factors
Sis: protooncogene for PDGF
tumor suppressor gene:
Genes that normally restrain cell growth but, when missing or inactivated by mutation, allow cells to grow uncontrolled.
Oncogenes
viral oncogene
A gene in the viral genome that contributes to malignancies in vertebrate hosts
proto-oncogenes (cellular-oncogene):
are normal cellular genes which promote normal growth and development
Oncogene and tumor suppressor gene
Oncogene:
also called cancer-promoting genes or transforming genes. A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens.
Activated Gα in turn activates an effector molecule. In a common example (shown here), the effector molecule is adenylyl cyclase - an enzyme in the inner face of the plasma membrane which catalyzes the conversion of ATP into the "second messenger" cyclic AMP (cAMP)
直接通过它们的
2
v-onc 结合到宿
主蛋白，并使后
者失活而发挥作
用。
Oncogenes
viral oncogene
A gene in the viral genome that contributes to malignancies in vertebrate hosts
proto-oncogenes (cellular-oncogene)
several tumors have receptors for PDGF resulting in AUTOC、IGF-1，2、TGF
Growth factor receptors
Including : PDGF、EGF、IGF-1，2、TGF, et al.
转化细胞的特征
decreased growth factor requirements loss of capacity for growth arrest - transformed
cells will continue to divide even when nutrients are limited (immortalization) loss of dependence on anchorage for growth can form colonies when suspended as single cells in agar changed cell morphology loss of contact inhibition
In the inactive state, Gα has GDP in its binding site.
When a hormone or other ligand binds to the associated GPCR, an allosteric change takes place in the receptor (that is, its tertiary structure changes).
肿瘤分子生物学 The molecular basis of
cancer
Jingbo Xiong, Ph. D.
Definition of cancer---by clinical workers
临床定义：是一类以生长不受控制、侵入 周围组织并向身体其它部位转移为特征的 疾病的总称；
三个特征：
Signal transducing proteins---Ras
Cause of cancer
Environmental agents
chemicals radiation viruses
Inherited
Genetic basis
tumor is clonal expansion of single progenitor cell that has genetic damage