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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Biol+Chem
2014 ; 289
(51
): 35193-204
Nephropedia Template TP
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English Wikipedia
MUC1 protein induces urokinase-type plasminogen activator (uPA) by forming a
complex with NF-?B p65 transcription factor and binding to the uPA promoter,
leading to enhanced invasiveness of cancer cells
#MMPMID25371209
Mori Y
; Akita K
; Tanida S
; Ishida A
; Toda M
; Inoue M
; Yashiro M
; Sawada T
; Hirakawa K
; Nakada H
J Biol Chem
2014[Dec]; 289
(51
): 35193-204
PMID25371209
show ga
Mucin 1 (MUC1) is overexpressed in various human malignant tumors and its
expression is correlated with a poor prognosis. MUC1 engages in signal
transduction by interacting with receptors for growth and differentiation
factors, which contributes to the growth and survival of cancer cells. However,
the mechanism by which MUC1 promotes cancer cell invasion remains unclear.
Microarray analysis revealed that expression of urokinase-type plasminogen
activator (uPA) was elevated in MUC1-overexpressing cells. Furthermore, up- and
down-modulation of MUC1 expression was clearly correlated with the change of uPA
expression. An immunochemical study showed that the distribution of uPA coincided
with that of MUC1 in various human cancer tissues. The MUC1 C-terminal domain
(MUC1-CD) was associated with nuclear factor-?B (NF-?B) p65 in MUC1-expressing
cells. Chromatin immunoprecipitation (ChIP) assays demonstrated that MUC1-CD
existed with NF-?B p65 on the uPA promoter. Luciferase assays indicated that the
uPA transcriptional activity was correlated with the level of MUC1 expression and
that this MUC1-enhancing effect on the uPA transcription was abolished by
introduction of mutations into the NF-?B binding sites on the uPA promoter. These
results indicate that formation of the MUC1-CD and NF-?B p65 complex enhanced
nuclear translocation of NF-?B p65 and subsequent occupancy of NF-?B binding
region on the uPA promoter, leading to elevated transcription of uPA. We also
demonstrated that uPA induced by MUC1 enhanced the matrix metalloproteinase
(MMP)-2 and -9 activities, and consequently promoted cancer cell invasion. Thus,
a MUC1 co-operating NF-?B signaling pathway plays a critical role in cancer cell
invasion in MUC1-expressing cells.