Deregulated expression of LRBA facilitates cancer cell growth.
LRBA expression is induced by mitogens in lymphoid and myeloid cells. The Drosophila LRBA orthologue rugose/DAKAP550 is involved in Notch, Ras and EGFR pathways. These findings suggest that LRBA could play a role in cell types that have increased proliferative and survival capacity. Here, we show by microarray and real-time PCR analyses that LRBA is overexpressed in several different cancers relative to their normal tissue controls. We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA. Furthermore, inhibition of LRBA expression by RNA interference, or inhibition of its function by a dominant-negative mutant, leads to significant growth inhibition of cancer cells, demonstrating that deregulated expression of LRBA contributes to the altered growth properties of a cancer cell. Finally, we show that the phosphorylation of EGFR is affected by the dominant-negative mutant, suggesting LRBA plays a role in the mammalian EGFR pathway. These findings demonstrate that LRBA facilitates cancer cell growth and thus LRBA may represent a novel molecular target for cancer therapy.
Wang
Jia-Wang
JW
Immunology Programs and Department of Interdisciplinary Oncology, H Lee Moffitt Comprehensive Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, FL 33612, USA.
Gamsby
Joshua J
JJ
Highfill
Steven L
SL
Mora
Linda B
LB
Bloom
Gregory C
GC
Yeatman
Tim J
TJ
Pan
Tien-chi
TC
Ramne
Anna L
AL
Chodosh
Lewis A
LA
Cress
W Douglas
WD
Chen
Jiandong
J
Kerr
William G
WG
D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference / Q000502:physiology; D011960:Receptors, Estrogen / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D011960:Receptors, Estrogen; D014157:Transcription Factors; C073446:protein p23; C428703:LRBA protein, human; D017868:Cyclic AMP-Dependent Protein Kinases