WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors.
Wnt family members are critical to many developmental processes, and components of the Wnt signaling pathway have been linked to tumorigenesis in familial and sporadic colon carcinomas. Here we report the identification of two genes, WISP-1 and WISP-2, that are up-regulated in the mouse mammary epithelial cell line C57MG transformed by Wnt-1, but not by Wnt-4. Together with a third related gene, WISP-3, these proteins define a subfamily of the connective tissue growth factor family. Two distinct systems demonstrated WISP induction to be associated with the expression of Wnt-1. These included (i) C57MG cells infected with a Wnt-1 retroviral vector or expressing Wnt-1 under the control of a tetracyline repressible promoter, and (ii) Wnt-1 transgenic mice. The WISP-1 gene was localized to human chromosome 8q24.1-8q24.3. WISP-1 genomic DNA was amplified in colon cancer cell lines and in human colon tumors and its RNA overexpressed (2- to >30-fold) in 84% of the tumors examined compared with patient-matched normal mucosa. WISP-3 mapped to chromosome 6q22-6q23 and also was overexpressed (4- to >40-fold) in 63% of the colon tumors analyzed. In contrast, WISP-2 mapped to human chromosome 20q12-20q13 and its DNA was amplified, but RNA expression was reduced (2- to >30-fold) in 79% of the tumors. These results suggest that the WISP genes may be downstream of Wnt-1 signaling and that aberrant levels of WISP expression in colon cancer may play a role in colon tumorigenesis.
Pennica
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Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. diane@gene.com
Swanson
T A
TA
Welsh
J W
JW
Roy
M A
MA
Lawrence
D A
DA
Lee
J
J
Brush
J
J
Taneyhill
L A
LA
Deuel
B
B
Lew
M
M
Watanabe
C
C
Cohen
R L
RL
Melhem
M F
MF
Finley
G G
GG
Quirke
P
P
Goddard
A D
AD
Hillan
K J
KJ
Gurney
A L
AL
Botstein
D
D
Levine
A J
AJ
D000595:Amino Acid Sequence; D000818:Animals; D055511:CCN Intercellular Signaling Proteins; D002461:Cell Line, Transformed; D003110:Colonic Neoplasms / Q000235:genetics*; D055513:Connective Tissue Growth Factor; D018076:DNA, Complementary / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016415:Sequence Alignment; D014162:Transfection; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
D055511:CCN Intercellular Signaling Proteins; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; C116396:CCN4 protein, human; C492067:CCN4 protein, mouse; D018076:DNA, Complementary; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; D055513:Connective Tissue Growth Factor