Title:
METHODS TO IDENTIFY COMPOUNDS USEFUL FOR TUMOR SENSITIZATION TO DNA DAMAGE
Document Type and Number:
WIPO Patent Application WO2005042701
Kind Code:
A3
Abstract:
Cdc25A is herein identified as a substrate for ß-TrCP1- or ß-TrCP2-mediated ubiquitination and subsequent degradation via the ubiquitin-proteasome pathway. In particular, it has been found that interfering with ß-TrCP expression or function, or increasing ß-TrCP degradation, leads to accumulation of Cdc25A in a cell. Since degradation of Cdc25A is a key feature of the response to DNA damage, leading to a stall in the cell cycle during which the cell can repair the damage, Cdc25A accumulation an abolish this response, thereby sensitizing the cell to DNA damage. Described herein are assays for identifying ß-TrCP inhibitors, and method of using such inhibitors for modulating Cdc25A degradation, sensitization of tumor cells, and as adjuvants in cancer therapy based on DNA damaging agents.
Inventors:
PAGANO MICHELE (US)
Application Number:
PCT/US2004/034801
Publication Date:
December 28, 2006
Filing Date:
October 19, 2004
Export Citation:
Assignee:
UNIV NEW YORK (US)
PAGANO MICHELE (US)
PAGANO MICHELE (US)
International Classes:
C12Q1/70; C12Q1/25; G01N33/50; G01N33/53; G01N33/566; C12N
Domestic Patent References:
| WO1999038969A1 | 1999-08-05 |
Other References:
RAY D. ET AL.: "Transforming Growth Factor Beta Facilitates Beta-TrCP-Mediated Degradation of Cdc25A in a Smad3-Dependent Manner", MOL CELL BIOL, vol. 25, no. 8, April 2005 (2005-04-01), pages 3338 - 3347, XP003004996
KANEMORI Y. ET AL.: "Beta-TrCP Recognizes a Previously Undescribed Nonphosphorylated Destruction Motif in Cdc25A and Cdc25B Phosphatases", PROC NATL ACAD SCI U S A, vol. 102, no. 18, May 2005 (2005-05-01), pages 6279 - 6284, XP003004997
BUSINO L. ET AL.: "Degradation of Cdc25A by Beta-TrCP During S Phase and in Response to DNA Damage", NATURE, vol. 426, no. 6962, November 2003 (2003-11-01), pages 87 - 91, XP003004998
KANEMORI Y. ET AL.: "Beta-TrCP Recognizes a Previously Undescribed Nonphosphorylated Destruction Motif in Cdc25A and Cdc25B Phosphatases", PROC NATL ACAD SCI U S A, vol. 102, no. 18, May 2005 (2005-05-01), pages 6279 - 6284, XP003004997
BUSINO L. ET AL.: "Degradation of Cdc25A by Beta-TrCP During S Phase and in Response to DNA Damage", NATURE, vol. 426, no. 6962, November 2003 (2003-11-01), pages 87 - 91, XP003004998
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