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.
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 humancancers.
Authors: Elsa De La Chesnaye; Juan Pablo Méndez; Ricardo López-Romero; María De Los Angeles Romero-Tlalolini; María Dolores Vergara; Mauricio Salcedo; Sergio R Ojeda Journal: Int J Clin Exp Pathol Date: 2015-09-01
Authors: Shahab Akhoondi; Linda Lindström; Martin Widschwendter; Martin Corcoran; Jonas Bergh; Charles Spruck; Dan Grandér; Olle Sangfelt Journal: Breast Cancer Res Date: 2010-12-01 Impact factor: 6.466
Authors: Richard S Maser; Bhudipa Choudhury; Peter J Campbell; Bin Feng; Kwok-Kin Wong; Alexei Protopopov; Jennifer O'Neil; Alejandro Gutierrez; Elena Ivanova; Ilana Perna; Eric Lin; Vidya Mani; Shan Jiang; Kate McNamara; Sara Zaghlul; Sarah Edkins; Claire Stevens; Cameron Brennan; Eric S Martin; Ruprecht Wiedemeyer; Omar Kabbarah; Cristina Nogueira; Gavin Histen; Jon Aster; Marc Mansour; Veronique Duke; Letizia Foroni; Adele K Fielding; Anthony H Goldstone; Jacob M Rowe; Yaoqi A Wang; A Thomas Look; Michael R Stratton; Lynda Chin; P Andrew Futreal; Ronald A DePinho Journal: Nature Date: 2007-05-21 Impact factor: 49.962
Authors: Jennifer O'Neil; Jonathan Grim; Peter Strack; Sudhir Rao; Deanne Tibbitts; Christopher Winter; James Hardwick; Markus Welcker; Jules P Meijerink; Rob Pieters; Giulio Draetta; Rosalie Sears; Bruce E Clurman; A Thomas Look Journal: J Exp Med Date: 2007-07-23 Impact factor: 14.307