Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma.
Targeted inactivation of Runx3 in mouse lung induced mucinous and nonmucinous adenomas and markedly shortened latency of adenocarcinoma formation induced by oncogenic K-Ras. RUNX3 was frequently inactivated in K-RAS mutated human lung adenocarcinomas. A functional genetic screen of a fly mutant library and molecular analysis in cultured cell lines revealed that Runx3 forms a complex with BRD2 in a K-Ras-dependent manner in the early phase of the cell cycle; this complex induces expression of p14(ARF)/p19(Arf) and p21(WAF/CIP). When K-Ras was constitutively activated, the Runx3-BRD2 complex was stably maintained and expression of both p14(ARF) and p21(WAF/CIP) was prolonged. These results provide a missing link between oncogenic K-Ras and the p14(ARF)-p53 pathway, and may explain how cells defend against oncogenic K-Ras.
Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju 361-763, South Korea.
You-Soub
YS
Lee
Jung-Won
JW
Lee
Ju-Won
JW
Jang
Xin-Zi
XZ
Chi
Jang-Hyun
JH
Kim
Ying-Hui
YH
Li
Min-Kyu
MK
Kim
Da-Mi
DM
Kim
Byeung-Sub
BS
Choi
Eung-Gook
EG
Kim
Jin-Haeng
JH
Chung
Ok-Jun
OJ
Lee
You-Mie
YM
Lee
Joo-Won
JW
Suh
Linda Shyue Huey
LS
Chuang
Yoshiaki
Y
Ito
Suk-Chul
SC
Bae
D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000107:Acetylation; D000230:Adenocarcinoma / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D056809:Alveolar Epithelial Cells / Q000502:physiology; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015870:Gene Expression; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020545:Respiratory Mucosa / Q000473:pathology; D014157:Transcription Factors; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
D020727:ADP-Ribosylation Factors; D050677:Core Binding Factor Alpha 3 Subunit; D019938:Cyclin D1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006655:Histone Deacetylases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D012097:Repressor Proteins; D014157:Transcription Factors; D018631:ras Proteins; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C530104:CCND1 protein, human; C493956:CDKN1A protein, human; C117307:KRAS protein, human; C493729:Runx3 protein, human; C493730:Runx3 protein, mouse; C400300:HDAC4 protein, human; C495971:Hras protein, mouse