Inhibition of gliomagenesis and attenuation of mitotic transition by MIIP.
The migration and invasion inhibitor protein (MIIP, also known as IIp45) was discovered as a negative regulator of cell migration and invasion in glioma. Our previous studies have shown that the MIIP protein was reduced or undetectable in some tissue samples obtained from patients with glioblastoma. The significance of MIIP in gliomagenesis is unknown. In this study, we report that MIIP has an important role in the inhibition of gliomagenesis and attenuation of mitotic transition. Increased MIIP expression levels inhibited colony formation and cell growth of glioma cell lines in vitro, whereas decreased expression by specific small interfering RNA for MIIP resulted in increased cell growth. Expression of MIIP in a glial-specific mouse model blocked glioma development and progression, thus showing that MIIP is an inhibitor of gliomagenesis. Furthermore, we show that MIIP attenuates mitotic transition and results in increased mitotic catastrophe. The biochemical mechanism of MIIP in this process is associated with its regulation of anaphase-promoting complex (APC/C) activity. MIIP interacts directly with Cdc20, and the interaction of MIIP with Cdc20 inhibits APC/C-mediated degradation of cyclin B1. Thus, MIIP attenuates mitotic transition and increases mitotic catastrophe, thereby inhibiting glioma development and progression.
Ji
P
P
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Smith
S M
SM
Wang
Y
Y
Jiang
R
R
Song
S W
SW
Li
B
B
Sawaya
R
R
Bruner
J M
JM
Kuang
J
J
Yu
H
H
Fuller
G N
GN
Zhang
W
W
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000737:chemistry / Q000378:metabolism; D018450:Disease Progression; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D009457:Neuroglia / Q000473:pathology; D009928:Organ Specificity; D055550:Protein Stability; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D002352:Carrier Proteins; D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D047908:Intracellular Signaling Peptides and Proteins; C480900:MIIP protein, human; D044767:Ubiquitin-Protein Ligases