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3p21.3 tumor suppressor gene H37/Luca15/RBM5 inhibits growth of human lung cancer cells through cell cycle arrest and apoptosis.
Cancer Res. 2006 Apr 01; 66(7):3419-27.CR

Abstract

Deletion at chromosome 3p21.3 is the earliest and the most frequently observed genetic alteration in lung cancer, suggesting that the region contains tumor suppressor gene(s) (TSG). Identification of those genes may lead to the development both of biomarkers to identify high-risk individuals and novel therapeutics. Previously, we cloned the H37/Luca15/RBM5 gene from 3p21.3 and showed its TSG characteristics. To investigate the physiologic function of H37 in the lung and its mechanism of tumor suppression, we have stably transfected H37 into A549 non-small cell lung cancer cells. A549/H37 cells show significant growth inhibition compared with the vector controls by in vitro and in vivo cell proliferation assays. Using this lung cancer cell model, we have found that the molecular mechanism of H37 tumor suppression involves both cell cycle (G(1)) arrest and apoptosis. To further define H37's function in cell cycle/apoptotic pathways, we investigated differential expression profiles of various cell cycle and apoptosis regulatory proteins using Western blot analysis. Both cyclin A and phophorylated RB levels were decreased in H37-transfected cells, whereas expression of Bax protein was increased. Mitochondrial regulation of apoptosis further downstream of Bax was investigated, showing change in the mitochondrial membrane potential, cytochrome c release into the cytosol, and enhanced caspase-9 and caspase-3 activities. We also report that H37 may mediate apoptosis in a p53-independent manner, and Bax knockdown by small interfering RNA suggests Bax plays a functional role downstream of H37. Lastly, we proposed a tumor suppression model of H37 as a post-transcriptional regulator for cell cycle/apoptotic-related proteins.

Authors+Show Affiliations

Division of Hematology/Oncology, University of California at Los Angeles School of Medicine, 675 Charles E. Young Drive South, Los Angeles, CA 90095, USA. julianaoh@mednet.ucla.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16585163

Citation

Oh, Juliana J., et al. "3p21.3 Tumor Suppressor Gene H37/Luca15/RBM5 Inhibits Growth of Human Lung Cancer Cells Through Cell Cycle Arrest and Apoptosis." Cancer Research, vol. 66, no. 7, 2006, pp. 3419-27.
Oh JJ, Razfar A, Delgado I, et al. 3p21.3 tumor suppressor gene H37/Luca15/RBM5 inhibits growth of human lung cancer cells through cell cycle arrest and apoptosis. Cancer Res. 2006;66(7):3419-27.
Oh, J. J., Razfar, A., Delgado, I., Reed, R. A., Malkina, A., Boctor, B., & Slamon, D. J. (2006). 3p21.3 tumor suppressor gene H37/Luca15/RBM5 inhibits growth of human lung cancer cells through cell cycle arrest and apoptosis. Cancer Research, 66(7), 3419-27.
Oh JJ, et al. 3p21.3 Tumor Suppressor Gene H37/Luca15/RBM5 Inhibits Growth of Human Lung Cancer Cells Through Cell Cycle Arrest and Apoptosis. Cancer Res. 2006 Apr 1;66(7):3419-27. PubMed PMID: 16585163.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3p21.3 tumor suppressor gene H37/Luca15/RBM5 inhibits growth of human lung cancer cells through cell cycle arrest and apoptosis. AU - Oh,Juliana J, AU - Razfar,Ali, AU - Delgado,Idolina, AU - Reed,Rebecca A, AU - Malkina,Anna, AU - Boctor,Baher, AU - Slamon,Dennis J, PY - 2006/4/6/pubmed PY - 2006/5/23/medline PY - 2006/4/6/entrez SP - 3419 EP - 27 JF - Cancer research JO - Cancer Res VL - 66 IS - 7 N2 - Deletion at chromosome 3p21.3 is the earliest and the most frequently observed genetic alteration in lung cancer, suggesting that the region contains tumor suppressor gene(s) (TSG). Identification of those genes may lead to the development both of biomarkers to identify high-risk individuals and novel therapeutics. Previously, we cloned the H37/Luca15/RBM5 gene from 3p21.3 and showed its TSG characteristics. To investigate the physiologic function of H37 in the lung and its mechanism of tumor suppression, we have stably transfected H37 into A549 non-small cell lung cancer cells. A549/H37 cells show significant growth inhibition compared with the vector controls by in vitro and in vivo cell proliferation assays. Using this lung cancer cell model, we have found that the molecular mechanism of H37 tumor suppression involves both cell cycle (G(1)) arrest and apoptosis. To further define H37's function in cell cycle/apoptotic pathways, we investigated differential expression profiles of various cell cycle and apoptosis regulatory proteins using Western blot analysis. Both cyclin A and phophorylated RB levels were decreased in H37-transfected cells, whereas expression of Bax protein was increased. Mitochondrial regulation of apoptosis further downstream of Bax was investigated, showing change in the mitochondrial membrane potential, cytochrome c release into the cytosol, and enhanced caspase-9 and caspase-3 activities. We also report that H37 may mediate apoptosis in a p53-independent manner, and Bax knockdown by small interfering RNA suggests Bax plays a functional role downstream of H37. Lastly, we proposed a tumor suppression model of H37 as a post-transcriptional regulator for cell cycle/apoptotic-related proteins. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/16585163/3p21_3_tumor_suppressor_gene_H37/Luca15/RBM5_inhibits_growth_of_human_lung_cancer_cells_through_cell_cycle_arrest_and_apoptosis_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16585163 DB - PRIME DP - Unbound Medicine ER -