Document Detail

Kinase requirements in human cells: II. Genetic interaction screens identify kinase requirements following HPV16 E7 expression in cancer cells.
MedLine Citation:
PMID:  18948598     Owner:  NLM     Status:  MEDLINE    
Human papillomavirus (HPV) oncoproteins subvert cellular signaling pathways, including kinase pathways, during the carcinogenic process. To identify kinases targeted by the HPV16 E7 oncoprotein, shRNA kinase screens were performed in RKO colorectal carcinoma cell lines that differ only in their expression of HPV16 E7. Our screens identified kinases that were essential for the survival of RKO cells, but not essential for RKO cells expressing HPV16 E7. These kinases include CDK6, ERBB3, FYN, AAK1, and TSSK2. We show that, as predicted, CDK6 knockdown inhibits pRb phosphorylation and induces S-phase depletion, thereby inhibiting cell viability. Knockdown of ERBB3, FYN, AAK1, and TSSK2 induces a similar loss of cell viability through an unknown mechanism. Expression of the HPV16 E7 oncoprotein, known to bind and degrade pRb, relieves the requirement of these kinases. These studies demonstate that expression of a single oncoprotein can dramatically alter kinase sensitivity in human cells. The shRNA screens used here perform analogously to genetic interaction screens commonly used in genetically tractable organisms such as yeast, and thus represent an exciting method for unbiased identification of cellular signaling pathways targeted by cancer mutations.
Amy Baldwin; Wenliang Li; Miranda Grace; Joseph Pearlberg; Ed Harlow; Karl Münger; Dorre A Grueneberg
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-10-23
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  105     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-29     Completed Date:  2008-12-01     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16478-83     Citation Subset:  IM    
The Channing Laboratory, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115.
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MeSH Terms
Cell Cycle
Cell Line, Tumor
Cell Survival
Neoplasms / pathology
Oncogene Proteins, Viral / genetics,  pharmacology*
Phosphotransferases / analysis,  genetics,  physiology*
RNA Interference
RNA, Small Interfering / pharmacology
Signal Transduction
Grant Support
Reg. No./Substance:
0/Oncogene Proteins, Viral; 0/RNA, Small Interfering; 0/oncogene protein E7, Human papillomavirus type 16; EC 2.7.-/Phosphotransferases

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