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细胞的抑制作用还可通过MAPK依赖性胰岛素反应
途径。Weng等¨列通过对乳腺癌模型的研究发现,
PTEN在胰岛素介导的信号转导途径中发挥独特作
用。在人乳腺癌细胞系7上皮性乳腺癌模型中,野
生型PTEN异位表达导致Akt磷酸化水平广泛抑制,
并且选择性抑制MAPK/ERK的磷酸化水平,而Akt
磷酸化水平受胰岛素和胰岛素生长因子1调控。
Bandyopadhyay等Ⅲ1在乳腺癌及前列腺癌中的研究
显示,PTEN上调肿瘤转移抑制基因Drg.1,而且
PTEN及Drg—l在临床标本中的表达呈显著正相关,
这也证明了PTEN可能通过上调Drg-l基因而发挥
其对乳腺癌转移的抑制作用。
5展望
PTEN基因通过P13K/Akt、MAPK/ERK、FAK等
途径发挥其脂质磷酸酶和蛋白磷酸酶活性。PTEN
基因及其蛋白表达异常与乳腺癌密切相关,野生型
PTEN基因能够对乳腺癌细胞产生抑制作用。但目
前对其详细的作用途径还没有完全明确,如对PTEN
的下游靶器的证明和PTEN在PDK-PTEN—Akt轴中
的基本角色认识仍不够完善,尚需深入研究。对
PTEN的转录规律、半衰期、细胞核区域化和PTEN
蛋白激活酶等的认知尚少。上述问题的解决将有助
于对PTEN的抑癌机制的阐明,更有助于肿瘤的早期
诊断和对肿瘤的基因治疗,对于研发新一代抗肿瘤
药物也具有重要的指导作用。
参考文献
[1]“J,Yen
C,Liaw
D,et a1.PrEN,a putative protein
tyresine
phos-
phatase
gene
mutated
in
human
brain,breast,and
prostate
cancer
[J].Science,1997,275(5308):1943-1947.
[2]Steck
PA,Pershouse MA,Jasser
SA,et
a1.Identification
of
a
candi—
date|unlour
suppressor gene,MMACI,at chromosome
10q23.3
that
is mutated in
multiple advanced
cancem[J].Nat
Genet,1997,
15(4):356-362.
[3]Li
DM,Sun
H.TEPI,encoded
by candidate
tumor suppressor
Io-
eus,is
a
Hovel
protein tyrosine
phosphata.se regulated by
transfor-
ming
growth
factor
B[J].Cancer
Res,1997,57(11):2124-2129.
[4]Chu
EC,Tarnawski
AS.mN
regulatory
functions in
tumor
sup-
pr∞sion and cell
biology[J].Med
Sci Monit,2004,10(10):
235-24l
[5]
[6]
[7]
Weng LP,Gimm O,Kum JB,el a/.Transient
ectopic expression
of
FIEN
in
thyroid
cancer
cell
lines
induces cell
cycle
arrest
and
cell
type-dependent
cell
death[J].Hum
Mol
Genet,2001。i0(3):251・
258.
1ijima
M.Huang YE,Luo
HR,el吐Novel
mechanism
of
mN
regulation
by
its
phosphatidylinositol 4,5-bisphosphate
binding mo-
tif
is
eritical for
chemotaxis[J].J
Biol Chem,2004,279(16):
16606一16613.
Lee
JO,Yang
H.Georgegcu
MM,el
02.Crystal structure
of
the
[8]
[9]
[10]
[12]
[13]
[14]
[15]
[16]
[17]
[21]
[22]
[23]
[24]
[25]
[26]
PrrEN
tumor
suppressor:implications for
its
phosphoinositide phos-
phat∞e
activity
and menlbFane
association[J].Cell,1999.99(3):
323-334.
Raftopoulou M.Etienne—Manneville
S,ScIf
A.el
a1.Regulation
of
cell
migration
by
the
C2
domain of
the tumor
suppressor
Pl卫N
[J].Science.2004,303(5661):1179-1181.
Valienle
M.Andres.Pans
A,Gomar
B。el
a1.Binding
of
mN
to
specific
PDZ
domains
contributes
to
P11EN
protein
stability and
phosphorylation by microtubule—associated
serine/threonine
kinases
[J].J
Biol
Chem,2005.280(32):28936-28943.
Meuillet口.Mahadevan
D,Berggeren
M.elal.Thioredoxin-I binds
to
the
C2 domain of PTEN
inhibiting
frrEN:lipid phosphataso
ac・
tivity
and
membrane binding
a
mechanism for
the funetional
l∞of
PrllE"s
tumor
suppressor
activity[J].Arch
Biochem
Biophys,
2004.429(2):123一133.
Hamada
K.Sasaki T,Koni
PA.el以.The PI'EN/P13K pathway
governs
normal vascular development and
tumor
angiogenesis[J】.
Genes Dev.2005,19(17):2054-2065.
Morrison DK.KSR:a MAPK scaffold of the Ras
pathway?[J].J
Cel
Science,2001.114(9):1609.1612.
Weng LP.Smith
WM.Brown儿.el
a1.FrI'EN
inhibits
insulirr
stim-
ulated
MEK/MAPK activation
and
cell
growth by blocking IRS.I
phosphorylation
and
lRS—l/Grb-2/Sos
complex
formation
in
a
breast
cancer
model【J】.Hum
Mol Genet,200I,10(6):605-616.
Tamura M,Gu J,Matsumoto
K,el
a/.Inhibition
of
eelJ
migration,
spreading,and focal
adhesions
by
tumor
suppressor
P1陋N[J】.sci・
ence.1998,280(5369):1614-1617.
Tamura
M,Gu
J.Danen EH,et a1.P1’ENinteractionswithfocal ad-
hesion
kinase
and
suppression of the extracellular matrix
dependent
phosphatidylinositol 3-kinase/Akt cell survival
pathway[J].J
Biol
Chem,1999,274(29):20693-20703.
Tamuta
M,Gu J,Tran
H,et a1.frrEN
gene
and intergrin
signaling
in
cancer[J].J
NatI
CancerInat.1999,91(21):1820—1828.
Wu
RC.Ij
X.Schonthal
AH.Transcriptional
activation
of
p2lWAFI
by
PTEN/MMACI tumor
suppressor[J].Mol
Cell
Bio--
chem.2000,203(1/2):59-71.
Bonneau
D,Langy
M.Mutation
of
the
human PTEN
gene[J].Hum
Mutat,2000,16(2):109-122.
Eng
C.Genetics of
Cowden syndrome:through the looking
gIm
of
oncology[J].Int
J
Oncol,1998,12(3):701.7lO.
All
IU.Schriml
LM.Dean
M,el a1.Mutational spectra of PlrEN/
MMACI
gene:a
tumor
suppressor
with
lipid
phosphatase activity
[J].J
Natl Cancer Inst,J999,91(22):1922-1932.
Teng
DH,Hu R.Un H.et
a1.MMACI/PTEN
mutation in
primary
tumor
specimens and
tumor
cell
lines[J].Cancer
Res,1997,57
(5):522l-5225.
Bose
S,Crane A.Hibshoosh H.el a/.Reduced
expression
of P1EN
correlates with
breast
cancer
progression[J].Hum
Pathol,2002。33
(4):405-409.
张雨杰,包永兴,管宇,等.乳腺浸润性导管癌P1'EN表达与临
床病理因素的关系[J].新疆医科大学学报,2009,32(2):
276-279.
Depowski PL,Rosenthal SI,Ross JS,el a/.10ss of
expression
ofthe
PrEN
gene
protein
product
is
associated
with
poor
outcome
in
breast
cancerI J】.Mod
Pathol,200l,14(7):672-676.
Petroeelli T.Slingerland JM.FrrEN
deficiency:a
role
in
mammary
carcinogenesis[J].Breast
Cancer Res,200l,3(6):356-360.
Bandyopadhyay S,Pal SK,Hirota
S.el
a1.f,rEN up—regulates the
tumor
metastasis
suppressor
gene
Drg—l
in
prostate
and
breast
cancerI
J
1.Cancer
Res,2004,64(21):7655-7660.
收稿日期:2009-05-03修回日期:2009.1l-05
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