Differential expression analysis of MIM (MTSS1) splice variants and a functional role of MIM in prostate cancer cell biology.
We previously identified MIM-A (missing in metastasis, MTSS1) by differential display techniques as missing in invasive, metastatic bladder cancer cell lines and suggested that MIM-A is a novel putative metastasis suppressor gene. Characterization of the MIM gene revealed a WH2 (Wiskott-Aldrich syndrome protein homology 2) domain in the C-terminus that is known to bind actin monomers and regulate organization of the actin cytoskeleton. Here, we further describe two alternatively splice variants of MIM-A, called MIM(12del) and MIM-B, which share > 50% amino acid sequence homology with MIM-A in the C-terminal domain. We show that expression of all three transcripts is down-regulated in prostate cancer cell lines and tumor samples from patients. In addition, we generated stably-transfected PC-3 cells overexpressing MIM-A to evaluate the importance of MIM-A in prostate cancer biology. The initial experiments show that expression of MIM decreased the number of actin filaments and was associated with a decrease in the G:F actin ratio. Overexpression of MIM-A had no effect on PC-3 cell adhesion to extracellular matrices, as well as no effect on PC-3 motility. Further, overexpression of MIM-A reduced the rate of PC-3 cell proliferation. These results support the hypothesis that MIM-A is an actin-binding protein and implicate a role of MIM-A in the regulation of cellular proliferation. These data suggest that the reduction of MIM-A gene expression in prostate cancer and other cancers may contribute to tumor growth and development, as well as metastasis.
Loberg
Robert D
RD
Department of Urology, University of Michigan Urology Center, 7431 CCGC, Ann Arbor, MI 48109-0946, USA. rloberg@umich.edu
Neeley
Chris K
CK
Adam-Day
Lashon L
LL
Fridman
Yaron
Y
St John
Lauren N
LN
Nixdorf
Sheri
S
Jackson
Paul
P
Kalikin
Linda M
LM
Pienta
Kenneth J
KJ
D000199:Actins / Q000378:metabolism; D017398:Alternative Splicing; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*
D000199:Actins; C486778:MTSS1 protein, human; D008840:Microfilament Proteins; D009363:Neoplasm Proteins