Cell Growth & Differentiation, Vol 7, Issue 7 871-878, Copyright © 1996 by American Association of Cancer Research

ARTICLES

Prohibitin in breast cancer cell lines: loss of antiproliferative activity is linked to 3' untranslated region mutations

ER Jupe, XT Liu, JL Kiehlbauch, JK McClung and RT Dell'Orco
Noble Center for Biomedical Research, Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.

The evolutionarily conserved prohibitin gene is located on human chromosome 17q21, and two alleles have been identified. Our previous studies characterizing prohibitin in immortalized cells, classified into four complementation groups (A-D) based on the ability of whole-cell hybrids to become senescent, have suggested that it has tumor suppressor activity in group B cells. Only the cell lines assigned to group B are sensitive to the antiproliferative activity of prohibitin, and all are homozygous for an allele designated B because of its exclusive association with this group. Prohibitin genotyping of 22 breast cancer cell lines identified 17 homozygous for the B allele, 5 homozygous for the non-B allele, and no heterozygotes. Four of these cell lines were chosen for further characterization of prohibitin. In cell proliferation assays, the homozygous B breast cancer cell lines (BT-20, SK-BR-3, and MCF7) are all inhibited from traversing the cell cycle following the introduction of wild-type prohibitin transcripts. The cell line homozygous for the alternative non-B allele (BT-549) is not inhibited by transcripts. All of the breast cancer cell lines overexpress the longer form of the prohibitin mRNA (1.9 kb) and the protein. Mutational analysis of the protein-coding region detected no mutations in any of the lines. However, BT-20, SK-BR-3, and MCF7 cells are all mutated in the final 200 bases of the 3' untranslated region (3'UTR) exclusive to the 1.9-kb transcript, but BT-549 cells had no alterations in this region of the 3'UTR. Functional mapping experiments performed in the mutated SK-BR-3 line showed that the wild-type 3'UTR alone is sufficient to inhibit cell cycle progression, indicating that the antiproliferative activity of the prohibitin transcript is localized to this region. Overall, our results show that most (80%) of the cell lines derived from breast tumors have a common prohibitin genotype, suggesting that they belong to the same group of immortalized cells, group B. The results also show that the prohibitin 3'UTR exhibits the characteristics of a trans-acting regulatory RNA (riboregulator), the tumor suppressor activity of which is inactivated by mutation in group B immortalized cells.

This article has been cited by other articles:

				J.-F. Lan, X.-C. Li, J.-J. Sun, J. Gong, X.-W. Wang, X.-Z. Shi, L.-J. Shi, Y.-D. Weng, X.-F. Zhao, and J.-X. Wang Prohibitin Interacts with Envelope Proteins of White Spot Syndrome Virus and Prevents Infection in the Red Swamp Crayfish, Procambarus clarkii J. Virol., December 1, 2013; 87(23): 12756 - 12765. [Abstract] [Full Text] [PDF]

				F. A. Karreth and P. P. Pandolfi ceRNA Cross-Talk in Cancer: When ce-bling Rivalries Go Awry Cancer Discovery, October 1, 2013; 3(10): 1113 - 1121. [Abstract] [Full Text] [PDF]

				N. Patel, S. K. Chatterjee, V. Vrbanac, I. Chung, C. J. Mu, R. R. Olsen, C. Waghorne, and B. R. Zetter Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells PNAS, February 9, 2010; 107(6): 2503 - 2508. [Abstract] [Full Text] [PDF]

				C. Osman, C. Merkwirth, and T. Langer Prohibitins and the functional compartmentalization of mitochondrial membranes J. Cell Sci., November 1, 2009; 122(21): 3823 - 3830. [Abstract] [Full Text] [PDF]

				S. Rastogi, B. Joshi, P. Dasgupta, M. Morris, K. Wright, and S. Chellappan Prohibitin Facilitates Cellular Senescence by Recruiting Specific Corepressors To Inhibit E2F Target Genes Mol. Cell. Biol., June 1, 2006; 26(11): 4161 - 4171. [Abstract] [Full Text] [PDF]

				S. Rastogi, B. Joshi, G. Fusaro, and S. Chellappan Camptothecin Induces Nuclear Export of Prohibitin Preferentially in Transformed Cells through a CRM-1-dependent Mechanism J. Biol. Chem., February 3, 2006; 281(5): 2951 - 2959. [Abstract] [Full Text] [PDF]

				I. G. Campbell, J. Allen, and D. M. Eccles Prohibitin 3' Untranslated Region Polymorphism and Breast Cancer Risk Cancer Epidemiol. Biomarkers Prev., November 1, 2003; 12(11): 1273 - 1274. [Full Text]

				S. Manjeshwar, D. E. Branam, M. R. Lerner, D. J. Brackett, and E. R. Jupe Tumor Suppression by the Prohibitin Gene 3'Untranslated Region RNA in Human Breast Cancer Cancer Res., September 1, 2003; 63(17): 5251 - 5256. [Abstract] [Full Text] [PDF]

				L. G. J. Nijtmans, L. de Jong, M. Artal Sanz, P. J. Coates, J. A. Berden, J. W. Back, A. O. Muijsers, H. van der Spek, and L. A. Grivell Prohibitins act as a membrane-bound chaperone for the stabilization of mitochondrial proteins EMBO J., June 1, 2000; 19(11): 2444 - 2451. [Abstract] [Full Text] [PDF]

				M. M. Montano, K. Ekena, R. Delage-Mourroux, W. Chang, P. Martini, and B. S. Katzenellenbogen An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens PNAS, June 8, 1999; 96(12): 6947 - 6952. [Abstract] [Full Text] [PDF]

				T. L. Sit, A. A. Vaewhongs, and S. A. Lommel RNA-Mediated Trans-Activation of Transcription from a Viral RNA Science, August 7, 1998; 281(5378): 829 - 832. [Abstract] [Full Text]