Deregulated expression of LRBA facilitates cancer cell growth

• Published in: Oncogene Vol. 23; no. 23; pp. 4089 - 4097
• Main Authors: Wang, Jia-Wang, Gamsby, Joshua J, Highfill, Steven L, Mora, Linda B, Bloom, Gregory C, Yeatman, Tim J, Pan, Tien-chi, Ramne, Anna L, Chodosh, Lewis A, Cress, W Douglas, Chen, Jiandong, Kerr, William G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.05.2004; Nature Publishing; Nature Publishing Group
• Subjects: Adaptor Proteins, Signal Transducing; Apoptosis; Base Sequence; Biological and medical sciences; Breast Neoplasms - metabolism; Cancer; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Biology; Cell Cycle Proteins; Cell growth; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; DNA-Binding Proteins - metabolism; E2F Transcription Factors; E2F1 Transcription Factor; Epidermal growth factor receptors; Estrogens; Female; Fundamental and applied biological sciences. Psychology; Genes; Growth inhibition; HeLa Cells; Human Genetics; Humans; Insects; Internal Medicine; Kinases; Medical research; Medicine; Medicine & Public Health; Mitogens; Molecular and cellular biology; Molecular Sequence Data; mRNA; Mutants; Mutation; Myeloid cells; Neoplasms - metabolism; Oncology; original-paper; Phosphorylation; Promoter Regions, Genetic; Proteins; Receptors, Estrogen - metabolism; RNA Interference - physiology; RNA-mediated interference; Transcription Factors - metabolism; Tumor necrosis factor-TNF; Tumors; United States > US; E2F; RNA interference; gene expression profiling; LRBA; P53; Gene silencing; TP53 Gene; Growth; Malignant tumor; Gene expression; Carcinogenesis; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207567

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.