Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer.
Gynecol Oncol
; 98(1): 124-8, 2005 Jul.
Article
in En
| MEDLINE
| ID: mdl-15913747
ABSTRACT
OBJECTIVE:
Archipelago (AGO, also known as hCdc4, Fbw7, or Sel-10) is an F-box containing component of the SCF complex implicated in the ubiquitination and proteolysis of cyclin E and c-Myc, and found to be mutated in 16% of endometrial carcinomas. We have previously reported somatic mutations in AGO in 3/10 ovarian cancer cell lines, but the frequency of such mutations in primary ovarian cancer is unknown.METHODS:
The coding sequence of AGO was analyzed in 95 primary sporadic ovarian tumors and 16 cases of familial ovarian cancer, and correlated with levels of cyclin E and c-Myc protein expression. Constructs encoding mutations in AGO were transfected into an AGO-null cell line to directly test their ability to regulate cyclin E and c-Myc levels.RESULTS:
Mutations were present in only 2 of 95 sporadic cases a premature stop within the WD domain (471 Ter) and a missense change near the F-box (S245T). Both primary tumor specimens containing these mutations showed high levels of cyclin E and c-Myc, but reconstitution of an AGO-null cell line with constructs encoding these mutations showed 471 Ter to be inactive in regulating endogenous cyclin E and c-Myc levels, while the S245T mutant was indistinguishable from wild-type. No germ-line mutations were found in familial cases of ovarian cancer.CONCLUSION:
Somatic AGO mutations are infrequent in primary ovarian cancers and are unlikely to contribute to familial ovarian cancer. Reconstitution experiments, rather than measuring tumor levels of cyclin E and c-Myc, provide an effective approach to determine the functional significance of AGO mutations identified in human cancers.
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Database:
MEDLINE
Main subject:
Ovarian Neoplasms
/
Cell Cycle Proteins
/
Ubiquitin-Protein Ligases
/
F-Box Proteins
/
Mutation
Limits:
Female
/
Humans
Language:
En
Year:
2005
Type:
Article