导图社区 Ras
这是一篇关于Ras的思维导图:Ras-GTP传递信号给Raf-P;Raf-p结合在KSR-PP2A处,传递信号给同在KSR上的MEK-2P+ERK-2P。
编辑于2022-04-21 00:01:35Ras-human disease
简单介绍
Benign Tumors
Generally localized and small
Fairly common (warts疣, colon polyps, etc.)
Do not break out of originating organ
Function very much like cells of origin
Generally are easily removed by surgery外科手术
Malignant Tumors
Remain localized for a time but thin invade surrounding tissue
Spread by forming metastases
Cells travel through circulation
Can invade any other body tissues
Produce few markers of original tissue
Very difficult to treat
Cancer metastasis
primary tumor invasion
EMT上皮间质转化
minimal极小的 residual disease
local recurrence复发
intravasation
circulating tumor cells
extravasation
micrometastasis
metastasis in secondary sites
autocrine
paracrine
肿瘤转移的常用检测方法 (不考)
Cancer
产生原因
Loss of cell-cycle control
Cloned cells divide unchecked
Results from multiple genetic mutations
Cell cycle genes
DNA repair genes
Apoptosis genes
Growth regulation genes
Metabolism
Epigenetic regulation
DNA methylation, non-coding RNAs, histone modification
是基因活动
Activation of oncogenes (continuous "go" signal)
癌基因(oncogene)
其编码区或调节区遗传性状发生改变,增加癌源性或转化潜能的基因
Inactivation of tumor suppressor genes (removes "stop" signal)
抑癌基因(Tumor-suppressor gene)
这类因功能丧失后引起肿瘤发生的基因称抑癌基因
p53
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas 小鼠肝癌的衰老和肿瘤清除是由p53恢复触发的
In addition to p53 loss, mutation of p53 was also detected in tumor samples
不同的蛋白在一起会有空间构象,p53的抗原表位可能会被遮盖掉
p53 Mutation Frequency in Various Cancers
Li–Fraumeni syndrome综合征
1969发现
the wide range of cancers found in affected families, the inherited higher risk of developing cancer among generations, and the relatively early age of the cancer diagnosis with nearly half of affected individuals having a cancer diagnosis before age 30.
癌症种类广泛
遗传风险高
诊断出癌症的年龄小
Approximately 70% of families with LFS will have a mutation (alteration) in the TP53 gene
Ras signaling
Ras
NRAS, HRAS, KRAS4A and KRAS4B
Raf
(ARAF, BRAF, RAF-1)
MEK
MEK1, MEK2
ERK
ERK1/2, ERK3/4, ERK5
Evolutionary Conservation of the MAPK Signaling pathway
具体的传递链条
EC Signal刺激到受体;受体得出adaptor proteins&exchange factors;因此Ras蛋白启动;分其他途径和MAPK途径
MAPK途径:Ras--MKKKs--MKKs--MAPKs(ERK)
nuclear Txn factors
kinases
structral proteins
other signaling proteins
Signaling pathway
三种Ras
Harvey sarcoma virus-associated oncogene : Ha-ras (H-ras in mammals)
Kirsten sarcoma virus : Ki-ras (K-ras in mammals)
N-ras: cloned from neuroblastoma成神经细胞瘤 and leukaemia cell lines
KRas, NRas, HRas share 90% homology, the C-terminus region -- hypervariable变异度高的
Ras and human cancers
Activating Ras mutations occur in 30% of human cancers.
pancreatic, colorectal, endometrial, lung and cervical cancers
KRAS
melanoma
NRAS
bladder cancer
HRAS
Ras与人体中不同部位的癌变息息相关,具体看ppt22,23
G12,Q61
Somatic activation of the K-ras oncogene causes early onset lung cancer in mice
K-ras exon 1 with an activating glycine to aspartic acid mutation at codon 12 (G12D) G12D出的甘氨酸突变成了天冬氨酸
somatic missense Ras mutations : amino-acid substitutions替换 at G12, G13 and Q61.
impair the intrinsic GTPase activity 损害内在酶活性
confer resistance to GAPs (GTPase activating protein)给GAPs抗性
causing cancer-associated mutant Ras proteins to accumulate in the active, GTP-bound conformation造成癌变相关的Ras积累
三个癌症的例子
Cardio-facio-cutaneous syndrome 心脏-脸-皮肤征候群
有问题的地方:KRAS, BRAF, MEK1, MEK2
特征
growth failure
distinctive facial appearance面容异常
Ectodermal abnormalities外胚层畸形
congenital heart defects 先天性心脏缺损
Not cancer-prone非癌变
Costello syndrome科斯特洛综合征
有问题的地方:HRAS
特征
delayed development and mental retardation 发育延迟精神迟滞
Typical facial appearance
loose skin
increased creases皱纹 of the hands
Rhabdomyosarcoma横纹肌肉瘤, neuroblastoma, ganglioneuroblastoma成神经节细胞瘤, bladder cancer
Noonan syndrome努南综合征
autosomal dominant disorder, 常染色体显性无序
比例:1/1000-1/2500
Mutations in the KRAS and PTPN11 genes cause Noonan syndrome
特征
unusual facial characteristics
short stature身高
heart defects
bleeding problems出血
skeletal malformations骨骼畸形
Eye abnormalities ( 95 % of patients)
Problems with language and speech are common
B-Raf mutations in human cancer
路径A
EGF与TK-4P结合,刺激结合在TK磷酸基团上的Grb2&SOS传递信号给Ras-GTP
Ras-GTP传递信号给Raf-P;Raf-p结合在KSR-PP2A处,传递信号给同在KSR上的MEK-2P+ERK-2P
ERK-2P接受信号后去磷酸化,产生四个ERK,进入细胞核中,传递信号给ELK-1+2P+SRF复合物;该复合物作用于DNA上调节基因转录
最终影响细胞增殖,生存,衰老,分化(proliferation,suvival,senescence,differentiation)
路径B
无EGF的情况下,这个时候TK上没有4个P;Grb2和SOS没有结合在一起,Ras-GDP(无能量)
V600E结合BRAF,刺激在KSR上的MEK-2P+ERK-2P
ERK去磷酸化进核,传递信号给ELK-1+2P+SRF复合物;该复合物作用于DNA上调节基因转录
最终使细胞转化tranformation
a valine (V) to a glutamic acid (E)缬氨酸变谷氨酸
看看ppt32对FDG PET的介绍
Ras-induced Transformed phenotypes 必考!!
Morphology 形态学(上的变化)
Loss of contact inhibition
注意这个时候还算不上是癌细胞 eg:NIH3T3 +H-Ras R12 是个可以无限增殖的细胞,但是不是肿瘤细胞
Adhesion
Anchorage-independent Growth 锚点非依赖
细胞不贴壁也能活
Growth
Tumor induction肿瘤产生 (nu/nu)
Cellular Senescence
什么是细胞衰老
定义:Response of normal cells to potentially cancer-causing events:
正常组织受到的影响变成initiated cell
telomere shortening端粒缩短
chromosomal perturbation染色体微扰
actvation of oncogenes
initiated cell走两条路
1.p53 pathway、p16/pRB pathway在起效用
细胞衰老,衰老的细胞
in the young: cancer prevention
in the elderly: organismal aging
2.上面两个路径失效,且有additional oncogenic stress
bypass绕过 of senscence
malignant transformation
首次描述:the Hayflick limit
没有虚线的部分是正常细胞系
虚线以后的无限增值是意外
Germ line 生殖细胞系
Early embryonic cells (stem cells)
Many tumor cells
看一下ppt37、38关于WI-38的介绍
第一个无限增殖的正常人类细胞
when cells exhaust their replicative life span,it will happen:
replicative senescence
Irreversible arrest不可逆终止 of cell proliferation (universal)
Resistance to apoptosis (stem cells)
Altered function功能改变 (universal but cell type specific)
Cellular Senescence: An important tumor suppressor mechanism
Induced by potentially oncogenic events
Most tumor cells are immortal
Many oncogenes act by allowing cells to bypassthe senescence response
Senescence is controlled by the two most important tumor suppressor genes -- p53 and pRB
Ras and senescence
Oncogene-induced senescence
细胞老化的特征
老化的细胞在型态上比正常的细胞大
包内空泡状结构增多
细胞停止复制DNA
细胞內的SA-β-galactosidase活性上升,若以beta-gal染色,细胞呈现蓝色 senescence-associated heterochromatic foci (SAHF) 阳性
Ras(V12) induce premature提前 senescence in primary fibroblasts
两种可能
Ras(V12)
在primary fibroblast中:p16,p19ARF,p53,p21---premature senescence
在immortal fibroblast中:deficiency缺乏 for INK4a,p19ARF or p53;or expressig E1A, c-Myc---eacape from senescence&oncogenic transformation
Oncogenic ras Provokes激起 Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a
染色方法:β-gal staining
发现IMR90、MEF、REF52也跟这条路径有关系
两条路径
The p16-cyclin D-pRb-E2F pathway.
The p53 pathway.
Both pathways are frequently deregulated in human cancer and regulate the cell cycle machinery机制 directly.
The mammalian cell cycle
The retinoblastastoma gene
定义:A tumor suppressor gene located on chromosome 13q14 that is mutated in many forms of cancer
Encodes a growth-inhibitory phosphoprotein:pRb
清除掉ppt49的疑问
Cell cycle regulated phosphorylation of the retinoblastoma protein
Cell Cycle Problems
正常状态:p16与CycD-CDK4结合,使得该激酶没有活性;p16离去后,CycD-CDK4有活性,使得Rb-E2F分离,Rb被磷酸化为Rb-3P
Rb-E2F:Repressor of transcription of proteins required for DNA synthesis
E2F:Activator of transcription of proteins needed for DNA synthesis
问题
Over expression of Cyclin D
Loss of p16 function
Loss of Rb function
重要路径(必考)
一些外界激活因素:tumor suppressors inactivation/oncogenes activation/ telomere dysfunction端粒功能紊乱/radiation辐射/chemotherapy/other factors
p19ARF抑制Mdm2,Mdm2抑制p53;但是p53会反过来促进Mdm2
p53导致衰老
p53激活p21,p21抑制Cyclin E/cdk2;Cyclin E/cdk2会抑制Rb
p16Ink4a抑制Cyclin D/cdk4,6;Cyclin D/cdk4,6抑制Rb
Rb抑制E2F
Rb促进衰老
Functional screen for rescue of Ras-induced senescence
休眠:进化上保守的抗死亡机制
线虫应对饥饿高温等应激时发生休眠
肿瘤转移中的休眠现象
细菌、真菌在遭遇应激刺激时进入休眠
间充质上皮转化蛋白(MET)是一种受体酪氨酸激酶
根源:肿瘤抗细胞死亡
癌症三大谜团
药物耐受
肿瘤转移
非肿瘤组织作用