PERSISTENT KINASE SIGNALS IN PC12 CELL DIFFERENTIATION
PERSISTENT KINASE SIGNALS IN PC12 CELL DIFFERENTIATION
批准号:
2459476
负责人:
LYNN E HEASLEY
金额:
$11.3万
依托单位国家:
美国
项目类别:
财政年份:
1993
资助国家:
美国
项目状态:
已结题
起止时间:
1993-08-01 至 1999-07-31
关键词:
PC12 cells SDS polyacrylamide gel electrophoresis biological signal transduction cell differentiation cell growth regulation enzyme activity enzyme substrate fibroblast growth factor growth factor receptors immunoprecipitation mitogen activated protein kinase neurotrophic factors phosphorylation platelet derived growth factor protein tyrosine kinase receptor expression western blottings
中文摘要
本提案的长期目标是确定具体的效应
英文摘要
The long-term goal of this proposal is to define the specific effector
enzymes and protein kinases involved in growth factor receptor-regulated
cell differentiation and growth. As a model system the PC12
pheochromocytoma cell line reversibly responds to nerve growth factor
(NGF) and basic fibroblast growth factor (bFGF) with partial growth arrest
in G1 and neurite extension while epidermal growth factor (EGF) and
insulin-like growth factor-I (IGF-I) fail to induce differentiation and
instead, exert modest mitogenic actions. All of these growth factors
signal through membrane-bound receptor tyrosine kinases. To date, the
specific signals that distinguish the differentiation action of NGF and
bFGF from the mitogenic actions of EGF and IGF-I remain poorly defined.
Recent findings in this lab indicate that the p42/44 mitogen-activated
protein (MAP) kinases are persistently activated and tyrosine
phosphorylated by growth factors that direct differentiation while
mitogens cause only transient activation of the pathway. Based on this
finding and the requirement for constant growth factor exposure to
maintain the differentiated PC12 cell phenotype, this proposal will test
the hypothesis that persistent activation of specific effector enzymes and
protein kinases discriminates those growth factors that induce
differentiation from those that exert mitogenic actions in PC12 cells. The
specific aims of the project are to l) identify the effector enzymes (GAP,
P13-K, PLCgamma, etc.) required for induction of PC12 cell differentiation
using mutant human PDGF receptors that lack the ability to activate one or
more effector enzymes. The betaPDGF receptor is a receptor tyrosine kinase
that is absent in parental PC12 cells, but directs reversible neurite
outgrowth, partial growth arrest and persistent MAP kinase activation
similar to NGF and bFGF when stably transfected into the cells. This
permits a molecular genetic strategy to dissect the elements of growth
factor receptor signal transduction involved in PC12 cell differentiation.
This proposal also seeks to 2) define the mechanism by which NGF, bFGF and
PDGF stimulate persistent phosphorylation and activation of the p42/44 MAP
kinases in differentiating PC12 cells. Recombinant p42 MAP kinase will be
used as a protein kinase substrate to identify and assay protein kinases
that phosphorylate and activate the MAP kinases. Also, the p54 MAP kinase
and p34-cdc2 protein kinases which are related to the p42/44 MAP kinases
will be examined for differential regulation by neurotrophic factors and
mitogens. Finally, 3) mutated forms of p42 MAP kinase that may exhibit
dominant-negative phenotypes will be expressed in PC12 cells to ascertain
the requirement for p42/44 MAP kinases in growth factor signalling of PC12
cell differentiation. Together, these aims will begin to define the
network of effectors and protein kinases that transduce the receptor
tyrosine kinase-stimulated signals in PC12 cells resulting in cell growth
and differentiation.
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In vivo regulation of MAP kinases in Ratus norvegicus renal papilla by water loading and restriction.
通过水加载和限制对褐鼠肾乳头中 MAP 激酶的体内调节。
DOI:
10.1172/jci4384
发表时间:
1998
期刊:
The Journal of clinical investigation
影响因子:
--
作者:
[Wojtaszek,PA, Heasley,LE, Berl,T]
通讯作者:
Berl,T
Hormonal regulation of MAP kinase in cultured rat inner medullary collecting tubule cells.
培养的大鼠内髓集合管细胞中 MAP 激酶的激素调节。
DOI:
10.1152/ajprenal.1994.267.3.f366
发表时间:
1994
期刊:
The American journal of physiology
影响因子:
--
作者:
[Heasley,LE, Senkfor,SI, Winitz,S, Strasheim,A, Teitelbaum,I, Berl,T]
通讯作者:
Berl,T
Multiple mitogen-activated protein kinases are regulated by hyperosmolality in mouse IMCD cells.
小鼠 IMCD 细胞中多种丝裂原激活蛋白激酶受高渗透压调节。
DOI:
10.1152/ajprenal.1997.272.3.f305
发表时间:
1997
期刊:
The American journal of physiology.
影响因子:
--
作者:
[Berl,T, Siriwardana,G, Ao,L, Butterfield,LM, Heasley,LE]
通讯作者:
Heasley,LE
c-Jun NH2-terminal kinase regulation of the apoptotic response of small cell lung cancer cells to ultraviolet radiation.
c-Jun NH2 末端激酶调节小细胞肺癌细胞对紫外线辐射的凋亡反应。
DOI:
10.1074/jbc.272.15.10110
发表时间:
1997
期刊:
The Journal of biological chemistry
影响因子:
--
作者:
[Butterfield,L, Storey,B, Maas,L, Heasley,LE]
通讯作者:
Heasley,LE
GTPase-deficient G alpha 16 and G alpha q induce PC12 cell differentiation and persistent activation of cJun NH2-terminal kinases.
GTPase 缺陷的 G α 16 和 G α q 诱导 PC12 细胞分化和 cJun NH2 末端激酶的持续激活。
DOI:
10.1128/mcb.16.2.648
发表时间:
1996
期刊:
Molecular and cellular biology
影响因子:
5.3
作者:
[Heasley,LE, Storey,B, Fanger,GR, Butterfield,L, Zamarripa,J, Blumberg,D, Maue,RA]
通讯作者:
Maue,RA
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