JCT  Vol.5 No.6 , May 2014
Oncomorphic TP53 Mutations in Gynecologic Cancers Lose the Normal Protein:Protein Interactions with the microRNA Microprocessing Complex
Abstract: Mutations in the tumor suppressor TP53 occur in almost all advanced ovarian cancers and in many advanced serous endometrial cancers. Mutations in TP53 can alter the function of the p53 protein, and some mutations result in a mutated protein with oncogenic activity. Previously referred to as gain of function (GOF) p53 proteins, we now term these “oncomorphic” mutations to better describe their function as oncogenes. We reviewed the data from The Cancer Genome Atlas (TCGA) and demonstrate that of the patients diagnosed with endometrial cancer that harbor TP53 mutations, approximately 30% of these mutations are oncomorphic. In ovarian cancer, approximately 20% are oncomorphic. The wild type (WT) p53 protein transactivates genes and micro-RNAs (miRNAs) necessary in the response to cellular stress, which turn off growth and induce apoptosis. In addition to direct transcriptional activation, WT p53 also acts through protein:protein interactions with Drosha and the miRNA processing complex to mediate rapid, enhanced processing of a subset of anti-growth miRNAs. We validated the interaction of WT p53 with the Drosha complex in the cell line UCI-107. We observed that miRNAs that inhibit the expression of oncogenes were induced. Specifically, some miRNAs were induced very rapidly over minutes, consistent with enhanced processing, while others required hours, consistent with transcriptional activation. In contrast, the most common oncomorphic TP53 mutations failed to interact with the Drosha complex and lost the ability to rapidly induce the miRNAs which inhibit oncogene expression. These studies highlight one mechanism underlying the oncomorphic properties of specific TP53 mutations: loss of the enhanced processing of anti-proliferative miRNAs.
Cite this paper: Brachova, P. , Mueting, S. , Devor, E. and Leslie, K. (2014) Oncomorphic TP53 Mutations in Gynecologic Cancers Lose the Normal Protein:Protein Interactions with the microRNA Microprocessing Complex. Journal of Cancer Therapy, 5, 506-516. doi: 10.4236/jct.2014.56058.

[1]   Siegel, R., Naishadham, D. and Jemal, A. (2012) Cancer Statistics, 2012. CA: A Cancer Journal for Clinicians, 62, 10-29.

[2]   Cancer Genome Atlas Research N (2013) Integrated Genomic Characterization of Endometrial Carcinoma. Nature, 497, 67-73.

[3]   Cancer Genome Atlas Research N (2011) Integrated Genomic Analyses of Ovarian Carcinoma. Nature, 474, 609-615.

[4]   Cai, X., Hagedorn, C.H. and Cullen, B.R. (2004) Human microRNAs Are Processed from Capped, Polyadenylated Transcripts That Can Also Function as mRNAs. RNA, 10, 1957-1966.

[5]   Lee, Y., Kim, M., Han, J., Yeom, K.H., Lee, S., Baek, S.H., et al. (2004) MicroRNA Genes Are Transcribed by RNA Polymerase II. EMBO Journal, 23, 4051-4060.

[6]   Kim, V.N. (2004) MicroRNA Precursors in Motion: Exportin-5 Mediates Their Nuclear Export. Trends in Cell Biology, 14, 156-159.

[7]   Yi, R., Qin, Y., Macara, I.G. and Cullen, B.R. (2003) Exportin-5 Mediates the Nuclear Export of Pre-microRNAs and Short Hairpin RNAs. Genes & Development, 17, 3011-3016.

[8]   Filipowicz, W., Bhattacharyya, S.N. and Sonenberg, N. (2008) Mechanisms of Post-Transcriptional Regulation by microRNAs: Are the Answers in Sight? Nature Reviews Genetics, 9, 102-114.

[9]   Suzuki, H.I. and Miyazono, K. (2010) Dynamics of microRNA Biogenesis: Crosstalk between p53 Network and Microrna Processing Pathway. Journal of Molecular Medicine, 88, 1085-1094.

[10]   Suzuki, H.I., Yamagata, K., Sugimoto, K., Iwamoto, T., Kato, S. and Miyazono, K. (2009) Modulation of microRNA Processing by p53. Nature, 460, 529-533.

[11]   Fukuda, T., Yamagata, K., Fujiyama, S., Matsumoto, T., Koshida, I., Yoshimura, K., et al. (2007) DEAD-Box RNA Helicase Subunits of the Drosha Complex Are Required for Processing of rRNA and a Subset of microRNAs. Nature Cell Biology, 9, 604-611.

[12]   Meng, X., Dizon, D.S., Yang, S., Wang, X., Zhu, D., Thiel, K.W., et al. (2013) Strategies for Molecularly Enhanced Chemotherapy to Achieve Synthetic Lethality in Endometrial Tumors with Mutant p53. Obstetrics and Gynecology International, 2013, Article ID: 828165.

[13]   Gaiddon, C., Lokshin, M., Ahn, J., Zhang, T. and Prives, C. (2001) A Subset of Tumor-Derived Mutant Forms of p53 Down-Regulate p63 and p73 through a Direct Interaction with the p53 Core Domain. Molecular Cell Biology, 21, 1874-1887.

[14]   Xie, T.X., Zhou, G., Zhao, M., Sano, D., Jasser, S.A., Brennan, R.G., et al. (2013) Serine Substitution of Proline at Codon 151 of TP53 Confers Gain of Function Activity Leading to Anoikis Resistance and Tumor Progression of Head and Neck Cancer Cells. Laryngoscope, 123, 1416-1423.

[15]   Scian, M.J., Stagliano, K.E., Deb, D., Ellis, M.A., Carchman, E.H., Das, A., et al. (2004) Tumor-Derived p53 Mutants Induce Oncogenesis by Transactivating Growth-Promoting Genes. Oncogene, 23, 4430-4443.

[16]   Lang, G.A., Iwakuma, T., Suh, Y.A., Liu, G., Rao, V.A., Parant, J.M., Valentin-Vega, Y.A., Terzian, T., Caldwell, L.C., Strong, L.C., El-Naggar, A.K. and Lozano, G. (2004) Gain of Function of a p53 Hot Spot Mutation in a Mouse Model of Li-Fraumeni Syndrome. Cell, 119, 861-872.

[17]   Olive, K.P., Tuveson, D.A., Ruhe, Z.C., Yin, B., Willis, N.A., Bronson, R.T., Crowley, D. and Jacks, T. (2004) Mutant p53 Gain of Function in Two Mouse Models of Li-Fraumeni Syndrome. Cell, 119, 847-860.

[18]   Li, B., Rosen, J.M., McMenamin-Balano, J., Muller, W.J. and Perkins, A.S. (1997) neu/ERBB2 Cooperates with p53-172H during Mammary Tumorigenesis in Transgenic Mice. Molecular and Cellular Biology, 17, 3155-3163.

[19]   Ko, J.L., Chiao, M.C., Chang, S.L., Lin, P., Lin, J.C., Sheu, G.T. and Lee, H. (2002) A Novel p53 Mutant Retained Functional Activity in Lung Carcinomas. DNA Repair, 1, 755-762.

[20]   Sproston, A.R., Boyle, J.M., Heighway, J., Birch, J.M. and Scott, D. (1996) Fibroblasts from Li-Fraumeni Patients Are Resistant to Low Dose-Rate Irradiation. International Journal of Radiation Biology, 70, 145-150.

[21]   Hanel, W., Marchenko, N., Xu, S., Yu, X.F., Weng, W. and Moll, U. (2013) Two Hot Spot Mutant p53 Mouse Models Display Differential Gain of Function in Tumorigenesis. Cell Death and Differentiation, 20, 898-909.

[22]   Song, H., Hollstein, M. and Xu, Y. (2007) p53 Gain-of-Function Cancer Mutants Induce Genetic Instability by Inactivating ATM. Nature Cell Biology, 9, 573-580.

[23]   Krepulat, F., Lohler, J., Heinlein, C., Hermannstadter, A., Tolstonog, G.V. and Deppert, W. (2005) Epigenetic Mechanisms Affect Mutant p53 Transgene Expression in WAP-mutp53 Transgenic Mice. Oncogene, 24, 4645-4659.

[24]   Bergamaschi, D., Gasco, M., Hiller, L., Sullivan, A., Syed, N., Trigiante, G., et al. (2003) p53 Polymorphism Influences Response in Cancer Chemotherapy via Modulation of p73-Dependent Apoptosis. Cancer Cell, 3, 387-402.

[25]   Irwin, M.S., Kondo, K., Marin, M.C., Cheng, L.S., Hahn, W.C. and Kaelin Jr., W.G. (2003) Chemosensitivity Linked to p73 Function. Cancer Cell, 3, 403-10. (03)00078-3

[26]   Duan, W., Ding, H., Subler, M.A., Zhu, W.G., Zhang, H., Stoner, G.D., Windle, J.J., Otterson, G.A. and Villalona-Calero, M.A. (2002) Lung-Specific Expression of Human Mutant p53-273H Is Associated with a High Frequency of Lung Adenocarcinoma in Transgenic Mice. Oncogene, 21, 7831-7838.

[27]   Morselli, E., Tasdemir, E., Maiuri, M.C., Galluzzi, L., Kepp, O., Criollo, A., Vicencio, J.M., Soussi, T. and Kroemer, G. (2008) Mutant p53 Protein Localized in the Cytoplasm Inhibits Autophagy. Cell Cycle, 7, 3056-3061.

[28]   Bourdon, J.C., Fernandes, K., Murray-Zmijewski, F., Liu, G., Diot, A., Xirodimas, D.P., Saville, M.K. and Lane, D.P. (2005) p53 Isoforms Can Regulate p53 Transcriptional Activity. Genes & Development, 19, 2122-2137.

[29]   Hofstetter, G., Berger, A., Fiegl, H., Slade, N., Zoric, A., Holzer, B., Schuster, E., Mobus, V.J., Reimer, D., Daxenbichler, G., Marth, C., Zeimet, A.G., Concin, N. and Zeillinger, R. (2010) Alternative Splicing of p53 and p73: The Novel p53 Splice Variant p53δ Is an Independent Prognostic Marker in Ovarian Cancer. Oncogene, 29, 1997-2004.

[30]   Holmila, R., Fouquet, C., Cadranel, J., Zalcman, G. and Soussi, T. (2003) Splice Mutations in the p53 Gene: Case Report and Review of the Literature. Human Mutation, 21, 101-102.

[31]   Sameshima, Y., Akiyama, T., Mori, N., Mizoguchi, H., Toyoshima, K., Sugimura, T., Terada, M. and Yokota, J. (1990) Point Mutation of the p53 Gene Resulting in Splicing Inhibition in Small Cell Lung Carcinoma. Biochemical and Biophysical Research Communications, 173, 697-703.

[32]   Nakayama, T., Toguchida, J., Wadayama, B., Kanoe, H., Kotoura, Y. and Sasaki, M.S. (1995) MDM2 Gene Amplification in Bone and Soft-Tissue Tumors: Association with Tumor Progression in Differentiated Adipose-Tissue Tumors. International Journal of Cancer, 64, 342-346.

[33]   He, X., He, L. and Hannon, G.J. (2007) The Guardian’s Little Helper: MicroRNAs in the p53 Tumor Suppressor Network. Cancer Research, 67, 11099-11101.

[34]   Kawai, S. and Amano, A. (2012) BRCA1 Regulates MicroRNA Biogenesis via the DROSHA Microprocessor Complex. Journal of Cell Biology, 197, 201-208.

[35]   Mendell, J.T. and Olson, E.N. (2012) MicroRNAs in Stress Signaling and Human Disease. Cell, 148, 1172-1187.

[36]   Wang, H., Tan, G., Dong, L., Cheng, L., Li, K., Wang, Z., et al. (2012) Circulating MiR-125b as a Marker Predicting Chemoresistance in Breast Cancer. PLoS ONE, 7, Article ID: e34210.

[37]   Chen, J., Wang, W., Zhang, Y., Chen, Y. and Hu, T. (2014) Predicting Distant Metastasis and Chemoresistance Using Plasma miRNAs. Medical Oncology, 31, 799.

[38]   Allen, K.E. and Weiss, G.J. (2010) Resistance May not Be Futile: MicroRNA Biomarkers for Chemoresistance and Potential Therapeutics. Molecular Cancer Therapeutics, 9, 3126-3136.