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  • Original Paper
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Deregulated expression of LRBA facilitates cancer cell growth

Oncogene volume 23, pages 4089–4097 (2004)Cite this article

Abstract

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.

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Abbreviations

AKAP:

A kinase anchor protein

BEACH:

beige And CHS

CHS1 :

Chediak–Higashi Syndrome 1

CNS:

central nervous system

EGFR:

epidermal growth factor receptor

ER:

estrogen receptor

FACS:

fluorescence-activated cell sorting

FAN:

factor associated with neutral sphingomyelinase

LRBA:

lipopolysaccharide-responsive and beige-like anchor

LvsA:

large volume sphere A

Nbea:

neurobeachin

PARP:

poly (ADP-ribose) polymerase

PH:

pleckstrin homology

RACE:

rapid amplification of cDNA ends

RB:

retinoblastoma protein

rg :

rugose

RNAi:

RNA interference

SHIP:

SH2-containing inositol phosphatase

shRNA:

small-hairpin RNA

siRNA:

small interfering RNA

SMART:

switching mechanism at 5′ end of RNA transcript

TNF:

tumor necrosis factor

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Acknowledgements

We thank Drs John Ninos, Steven Enkemann and Edward R Seijo for technical advice and assistance on flow cytometry analysis, microarray analysis and analytic microscopy, respectively. Various portions of this work were assisted by the Molecular Biology, Cytometry Microarray and Analytic Microscopy Core Facilities at the H Lee Moffitt Cancer Center & Research Institute. This work was supported in part by grants from the NIH RO1 DK54767, RO1 HL72523 and PO1 NS27405. WGK is The Newman Scholar of the Leukemia and Lymphoma Society.

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  1. Contributed equally to this work

Authors and Affiliations

  1. Immunology Programs, Tampa, 33612, FL, USA

    Jia-Wang Wang, Joshua J Gamsby, Steven L Highfill & William G Kerr

  2. Department of Interdisciplinary Oncology, H Lee Moffitt Comprehensive Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, 33612, FL, USA

    Jia-Wang Wang, Steven L Highfill, Linda B Mora, Gregory C Bloom, Tim J Yeatman, W Douglas Cress, Jiandong Chen & William G Kerr

  3. Department of Biochemistry, University of South Florida College of Medicine, Tampa, 33612, FL, USA

    Joshua J Gamsby, W Douglas Cress, Jiandong Chen & William G Kerr

  4. Molecular Oncology Programs, Tampa, 33612, FL, USA

    Linda B Mora, W Douglas Cress & Jiandong Chen

  5. Gastrointestinal Programs, Tampa, 33612, FL, USA

    Gregory C Bloom & Tim J Yeatman

  6. Abramson Family Cancer Research Institute and Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, 19104-6160, PA, USA

    Tien-chi Pan, Anna L Ramne & Lewis A Chodosh

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Correspondence to William G Kerr.

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Wang, JW., Gamsby, J., Highfill, S. et al. Deregulated expression of LRBA facilitates cancer cell growth. Oncogene 23, 4089–4097 (2004). https://doi.org/10.1038/sj.onc.1207567

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