PTEN TUMOR SUPPRESSOR AND SIGNAL TRANSDUCTION
PTEN TUMOR SUPPRESSOR AND SIGNAL TRANSDUCTION
批准号:
6856567
负责人:
Ramon E Parsons
金额:
$26.71万
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-03-01 至 2006-02-28
关键词:
Adenoviridaebiological signal transductioncytokine receptorsenzyme activitygene targetinggenetically modified animalshormone regulation /control mechanisminsulininsulin receptorinsulinlike growth factorlaboratory mouseneoplasm /canceroligonucleotidesoncoproteinsphosphatidylinositol 3 kinasephosphatidylinositolsphosphomonoesterasesprotein kinasetransfection /expression vectortumor suppressor proteins
中文摘要
描述:(改编自研究者摘要)PTEN/MMAC 1是一种肿瘤
在多种癌症中突变的抑制基因。PTEN编码磷酸酶
认识到重要的第二信使,
磷脂酰肌醇-3,4,5-三磷酸(PIP 3,4,5),并去除
肌醇环上的3 '-磷酸。因此,PTEN拮抗
磷脂酰肌醇(PI)-3激酶,其在磷酸化肌醇环时,
同样的位置。尽管PI-3激酶和PTEN可能影响许多
信号通路,也许是最好理解的通路种类,PTEN作用于
胰岛素受体和PI-3激酶的下游和AKT的上游。通过
底物的磷酸化,AKT调节许多参与的靶点,
转录、翻译、细胞周期和凋亡。测试
假设PTEN调节基因表达,他们开发了一种腺病毒
系统在感染后两小时内表达PTEN-/-肿瘤
细胞PTEN表达与AKT的快速抑制相关。标记
将不同感染时间的RNA与寡核苷酸芯片杂交
代表了超过四万个基因通过比较
未感染的细胞、腺-β-半乳糖苷酶和腺-PTEN感染的细胞,它们
确定了32名候选人,这些候选人在3小时内至少被诱导了三次。
感染他们为24名候选人准备了探针,其中8名
在北方印迹上证实了PTEN特异性诱导。最易诱导的基因
胰岛素受体底物(IRS)-2。IRS-2的诱导作用在
蛋白质水平。IRS-2是IRS基因家族的一员,其功能是
传递胰岛素、胰岛素样生长因子和细胞因子受体的衔接蛋白
信号. IRS-2的主要作用是将活化的受体与PI-3连接
激酶。在PTEN感染的细胞中,诱导的IRS-2与
PI-3激酶。因此,他们的初步数据表明,
诱导反馈回路激活PI-3激酶。本补助金申请将
本研究旨在探讨PTEN对IRS-2的调控机制,并对PTEN在IRS-2中的作用机制进行初步探讨。
IRS-2在肿瘤发生中的作用。他们将使用重组腺病毒,
药理学试剂,以确定细胞能够通过其
诱导IRS 2应答PTEN。这将包括使用腺病毒,
表达PTEN突变、显性阴性AKT和显性活性FKHR、GSK-3,
和RAF。还将测试PI-3激酶、MEK和mTOR的抑制剂。他们
他们不仅会分析这些药物诱导IRS-2的能力,
还比较了它们与PTEN对AKT、MAPK、GSK-3和S6的影响
激酶活性PI-3激酶和AKT的p85和p110亚基是有效的
致癌基因为了确定IRS-2在癌症中是否发生了基因改变,
将在细胞系和原发性肿瘤中筛选突变和影响,
含有野生型PTEN。因为IRS-2在细胞内起着衔接蛋白的作用,
他们将研究PTEN对胰岛素信号转导的影响,
小鼠的胰岛素信号传导。最后,PTEN杂合子小鼠在
多器官系统他们将用IRS-2+/-小鼠饲养PTEN+/-小鼠,
IRS-2缺失是否能够减弱肿瘤表型。
英文摘要
DESCRIPTION: (Adapted from the investigator's abstract) PTEN/MMAC1 is a tumor
suppressor that is mutated in many forms of cancer. PTEN encodes a phosphatase
that recognizes the important second messenger,
phosphatidylinositol-3,4,5-triphosphate (PIP3,4,5), and removes the
3'-phosphate from the inositiol ring. PTEN therefore antagonizes
phosphatidylinositol (PI)-3 kinase, which phosphorylates the inositol ring at
the same position. Although PI-3 kinase and PTEN potentially influence many
signaling pathways, perhaps the best understood pathway species, PTEN acts
downstream of the insulin receptor and PI-3 kinase and upstream of AKT. Through
the phosphorylation of substrates, AKT regulates many targets involved in
transcription, translation, the cell cycle, and apoptosis. To test the
hypothesis that PTEN regulates gene expression, they developed an adenoviral
system that expressed PTEN within two hours of infection in PTEN-/- tumor
cells. PTEN expression was associated with a rapid inhibition of AKT. Labeled
RNAs from different times of infection were hybridized to oligonucleotide chips
representing over 40,000 genes. By comparing the level of expression between
uninfected, Adeno-beta-galactosidase, and Adeno-PTEN infected cells, they
identified 32 candidates that were induced at least threefold within 3 hours of
infection. They prepared probes for 24 of the candidates, of which 8
demonstrated PTEN-specific induction on Northern blots. The most induced gene
was the insulin receptor substrate (IRS)-2. Induction of IRS-2 was confirmed at
the protein level. IRS-2 is a member of a family of IRS genes that function as
adaptor proteins for the transmission of insulin, IGF, and cytokine receptor
signals. The major role of IRS-2 is to link an activated receptor to PI-3
kinase. In PTEN infected cells, the induced IRS-2 coimmunoprecipitated with
PI-3 kinase. Thus, their preliminary data suggests that the expression of PTEN
induced a feedback-loop to activated PI-3 kinase. This grant application will
attempt to explore the mechanism through which PTEN regulates IRS-2 and define
the role of IRS-2 in tumorigenesis. They will use recombinant adenoviruses and
pharmacological agents to identify the mode through which cells are able to
induce IRS2 in response to PTEN. This will include the use of adenoviruses that
express PTEN mutations, dominant-negative AKT and dominant active FKHR, GSK-3,
and RAF. Inhibitors of PI-3 kinase, MEK, and mTOR will also be tested. They
will not only analyze these agents for their ability to induce IRS-2, they will
also compare them to PTEN regarding their effect on AKT, MAPK, GSK-3, and S6
kinase activity. The p85 and p110 subunits of PI-3 kinase and AKT are potent
oncogenes. To determine whether IRS-2 is altered genetically in cancer they
will screen for mutations and implications in cells lines and primary tumors
containing wild type PTEN. Because IRS-2 functions as an adapter protein in the
transduction of insulin signals, they will investigate the effect of PTEN on
insulin signaling in mice. Finally, PTEN heterozygous mice have tumors in
multiple organ systems. They will breed PTEN+/- mice with IRS-2+/- mice to see
if IRS-2 loss is able to attenuate the tumor phenotype.
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PTEN and Cancer
-
批准号:10462569
-
项目类别:
-
资助金额:$99.17万
-
财政年份:2017
-
负责人:Ramon E Parsons
-
依托单位:
PTEN and Cancer
-
批准号:10686280
-
项目类别:
-
资助金额:$99.17万
-
财政年份:2017
-
负责人:Ramon E Parsons
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依托单位:
PTEN and Cancer
-
批准号:9676731
-
项目类别:
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资助金额:$6.99万
-
财政年份:2017
-
负责人:Ramon E Parsons
-
依托单位:
PTEN and Cancer
-
批准号:10227679
-
项目类别:
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资助金额:$101.2万
-
财政年份:2017
-
负责人:Ramon E Parsons
-
依托单位:
PTEN and Cancer
-
批准号:9759839
-
项目类别:
-
资助金额:$98.16万
-
财政年份:2017
-
负责人:Ramon E Parsons
-
依托单位:
PTEN and Cancer
-
批准号:9390180
-
项目类别:
-
资助金额:$64.48万
-
财政年份:2017
-
负责人:Ramon E Parsons
-
依托单位:
THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT
-
批准号:10674487
-
项目类别:
-
资助金额:$263.84万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT
-
批准号:10229103
-
项目类别:
-
资助金额:$25.0万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
Developmental Funds
-
批准号:10454175
-
项目类别:
-
资助金额:$52.76万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
The Tisch Cancer Institute - Cancer Center Support Grant
-
批准号:9753966
-
项目类别:
-
资助金额:$237.3万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT
-
批准号:10293870
-
项目类别:
-
资助金额:$25.0万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT
-
批准号:10293872
-
项目类别:
-
资助金额:$25.0万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
Identifying immune correlates of disease severity and novel immune drivers of pathogenicity to target in patients with COVID-19
-
批准号:10164208
-
项目类别:
-
资助金额:$42.38万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
The Tisch Cancer Institute - Cancer Center Support Grant
-
批准号:9757864
-
项目类别:
-
资助金额:$22.5万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
Leadership, Planning and Evaluation
-
批准号:10674516
-
项目类别:
-
资助金额:$29.49万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
The Tisch Cancer Institute - Cancer Center Support Grant
-
批准号:9906318
-
项目类别:
-
资助金额:$25.0万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT
-
批准号:10454159
-
项目类别:
-
资助金额:$263.84万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
Leadership, Planning and Evaluation
-
批准号:10454176
-
项目类别:
-
资助金额:$29.49万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT
-
批准号:10293869
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
THE TISCH CANCER INSTITUTE - CANCER CENTER SUPPORT GRANT
-
批准号:10022654
-
项目类别:
-
资助金额:$263.84万
-
财政年份:2015
-
负责人:Ramon E Parsons
-
依托单位:
海外基金