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242 results on '"DePinho, R. A."'

3. Pyruvate Kinase M1 Suppresses Development and Progression of Prostate Adenocarcinoma

Author

Davidson, S. M., Schmidt, D. R., Heyman, J. E., O'Brien, J.P., Liu, A.C., Israelsen, W. J., Dayton, T. L., Sehgal, R., Bronson, R.T., Freinkman, E., Mak, H. H., Fanelli, G. N., Malstrom, S., Bellinger, G., Carracedo, A., Pandolfi, P. P., Courtney, K. D., Jha, A., DePinho, R. A., Horner, J. W., Thomas, C. J., Cantley, L.C., Loda, M., and Vander Heiden, M. G.

Subjects
Male, Cancer Research, Oncology, Carcinogenesis, Pyruvate Kinase, Prostate, Humans, Prostatic Neoplasms, Adenocarcinoma
Abstract

Altered metabolism helps sustain cancer cell proliferation and survival. Most cancers, including prostate cancers, express the M2 splice isoform of pyruvate kinase (PKM2), which can support anabolic metabolism to support cell proliferation. However, Pkm2 expression is dispensable for the formation and growth of many cancers in vivo. Expression of pyruvate kinase isoform M1 (Pkm1) is restricted to relatively few tissues and has been reported to promote growth of select tumors, but the role of PKM1 in cancer has been less studied than PKM2. To test how differential expression of pyruvate kinase isoforms affects cancer initiation and progression, we generated mice harboring a conditional allele of Pkm1 and crossed these mice, or those with a Pkm2 conditional allele, with a Pten loss-driven prostate cancer model. Pkm1 loss led to increased PKM2 expression and accelerated prostate cancer development, whereas Pkm2 deletion led to increased PKM1 expression and suppressed tumor progression. Metabolic profiling revealed altered nucleotide levels in tumors with high PKM1 expression, and failure of these tumors to progress was associated with DNA replication stress and senescence. Consistent with these data, a small molecule pyruvate kinase activator that mimics a high activity PKM1-like state suppressed progression of established prostate tumors. Analysis of human specimens showed PKM2 expression is retained in most human prostate cancers. Overall, this study uncovers a role for pyruvate kinase isoforms in prostate cancer initiation and progression, and argues that pharmacologic pyruvate kinase activation may be beneficial for treating prostate cancer. Significance: Differential expression of PKM1 and PKM2 impacts prostate tumorigenesis and suggests a potential therapeutic vulnerability in prostate cancer.

Published
2022

4. A Biochemical and Biological Analysis of Myc Superfamily Interactions

Author

Schreiber-Agus, N., Alland, L., Muhle, R., Goltz, J., Chen, K., Stevens, L., Stein, D., DePinho, R. A., Compans, R. W., editor, Cooper, M., editor, Hogle, J. M., editor, Koprowski, H., editor, Ito, Y., editor, Melchers, F., editor, Oldstone, M., editor, Olsnes, S., editor, Potter, M., editor, Saedler, H., editor, Vogt, P. K., editor, Wagner, H., editor, Potter, Michael, editor, and Melchers, Fritz, editor

Published
1997
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10. The WNT receptor ROR2 drives the interaction of multiple myeloma cells with the microenvironment through AKT activation

Author

Frenquelli, M., primary, Caridi, N., additional, Antonini, E., additional, Storti, F., additional, Viganò, V., additional, Gaviraghi, M., additional, Occhionorelli, M., additional, Bianchessi, S., additional, Bongiovanni, L., additional, Spinelli, A., additional, Marcatti, M., additional, Belloni, D., additional, Ferrero, E., additional, Karki, S., additional, Brambilla, P., additional, Martinelli-Boneschi, F., additional, Colla, S., additional, Ponzoni, M., additional, DePinho, R. A., additional, and Tonon, G., additional

Published
2019
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12. Differential Expression of myc-family Genes During Development: Normal and Deregulated N-myc Expression in Transgenic Mice

Author

Dildrop, R., Zimmerman, K., DePinho, R. A., Yancopoulos, G. D., Tesfaye, A., Alt, F. W., Compans, R. W., editor, Cooper, M., editor, Koprowski, H., editor, McConell, I., editor, Melchers, F., editor, Oldstone, M., editor, Olsnes, S., editor, Saedler, H., editor, Vogt, P. K., editor, Wagner, H., editor, Wilson, I., editor, Potter, Michael, editor, and Melchers, Fritz, editor

Published
1988
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13. POMHEX, a cell-permeable enolase inhibitor for collateral lethality targeting of ENO1-deleted glioblastoma

Author

Lin, Y.H., primary, Satani, N., additional, Hammoudi, N., additional, Pisaneschi, F., additional, Leonard, P., additional, Maxwell, D., additional, Peng, Z., additional, Link, T., additional, Lee, G., additional, Sun, D., additional, Marszalek, J., additional, Sun, Y., additional, McMurray, J., additional, Mandal, P., additional, Di Francesco, M., additional, Czako, B., additional, Wang, A., additional, Bornmann, W., additional, DePinho, R., additional, and Muller, F., additional

Published
2016
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14. Comprehensive genome-wide profile of regional gains and losses in multiple myeloma using array-CGH: The 1q21 amplification and potential role of the BCL-9 gene in multiple myeloma pathogenesis

Author

Carrasco R, Tonon G, Brennan C, Protopopov A, Sinha R, Feng B, Leo C, Zhang YY, Zhang J, Zhan FH, Protopopova M, Mitsiades C, Munshi N, Chin L, Bergsagel P, Kuehl M, Shaughnessy J, Anderson K, DePinho R, Carrasco, R, Tonon, G, Brennan, C, Protopopov, A, Sinha, R, Feng, B, Leo, C, Zhang, Yy, Zhang, J, Zhan, Fh, Protopopova, M, Mitsiades, C, Munshi, N, Chin, L, Bergsagel, P, Kuehl, M, Shaughnessy, J, Anderson, K, and Depinho, R

Published
2004

15. Towards patient-based cancer therapeutics

Author

Discovery, C. T., Network, D., Schreiber, S. L., Shamji, A. F., Clemons, P. A., Hon, C., Koehler, A. N., Munoz, B., Palmer, M., Stern, A. M., Wagner, B. K., Powers, S., Lowe, S. W., Guo, X., Krasnitz, A., Sawey, E. T., Sordella, R., Stein, L., Trotman, L. C., Califano, A., Dalla Favera, R., Ferrando, A., Iavarone, A., Pasqualucci, Laura, Silva, J., Stockwell, B. R., Hahn, W. C., Chin, L., Depinho, R. A., Boehm, J. S., Gopal, S., Huang, A., Root, D. E., Weir, B. A., Gerhard, D. S., Zenklusen, J. C., Roth, M. G., White, M. A., Minna, J. D., Macmillan, J. B., and Posner, B. A.

Subjects
Biomedical Engineering, MEDLINE, Bioengineering, Antineoplastic Agents, Bioinformatics, Small Interfering, Applied Microbiology and Biotechnology, Article, Mice, Neoplasms, Drug Discovery, medicine, Animals, Humans, Gene Regulatory Networks, Precision Medicine, RNA, Small Interfering, Drug discovery, business.industry, Animal, Cancer, Individualized Medicine, Precision medicine, medicine.disease, National Cancer Institute (U.S.), United States, Neoplasm Proteins, Cancer drug discovery, Disease Models, Animal, Disease Models, Molecular Medicine, RNA, business, Biotechnology
Abstract

A new approach to the discovery of cancer therapeutics is emerging that begins with the cancer patient. Genomic analysis of primary tumors is providing an unprecedented molecular characterization of the disease. The next step requires relating the genetic features of cancers to acquired gene and pathway dependencies and identifying small-molecule therapeutics that target them.

Published
2010

16. ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence

Author

Anver, M., Dickins, R., DePinho, R. A., Bennett, D. C., Merlino, G., Ichikawa, T., Sharpless, N. E., Sviderskaya, E. V., Ha, L., Lowe, S., and Krimpenfort, P.

Abstract

Inactivation of the p53 pathway represents the most common molecular defect of human cancer. But in the setting of melanoma, a highly aggressive and invariably fatal malignancy in its advanced disseminated form, mutation/deletion of p53 is relatively rare, whereas its positive regulator ARF is often lost. Here, we show that genetic deficiency in Arf but not p53 facilitates rapid development of melanoma in a genetically engineered mouse model. This difference is accounted for, at least in part, by the unanticipated observation that, unlike fibroblasts, senescence control in melanocytes is strongly regulated by Arf and not p53. Moreover, oncogenic NRAS collaborates with deficiency in Arf, but not p53, to fully transform melanocytes. Our data demonstrate that ARF and p53, although linked in a common pathway, suppress tumorigenesis through distinct, lineage-dependent mechanisms and suggest that ARF helps restrict melanoma progression by executing the oncogene-induced senescence program in benign nevi. Thus, therapeutics designed to restore wild-type p53 function may be insufficient to counter melanoma and other malignancies in which ARF holds p53-independent tumor suppressor activity.

Published
2007
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18. Mouse models for the study of telomerase

Author

Maria A. Blasco, Hw, Lee, Rizen M, Hanahan D, DePinho R, and Cw, Greider

Subjects
Enzyme Activation, Mice, Knockout, Mice, Models, Genetic, Disease Progression, Animals, RNA, Mice, Transgenic, Telomerase, Neoplasm Staging
Abstract

The ends of chromosomes, or telomeres, consist of short repeated sequences that are synthesized by a ribonucleoprotein-DNA polymerase called telomerase. The RNA component of telomerase is essential for enzyme activity. The maintenance of telomere length by telomerase has been proposed to be essential for cellular viability and to play an important role in cellular senescence and immortalization. We are interested in using the mouse as a model system for the study of telomerase. We studied telomerase activity and expression of the mouse telomerase RNA component (mTR) in two different transgenic mouse models of multistage tumorigenesis: models of islet cell carcinoma and squamous cell carcinoma. In both tumour models, telomerase activity was detected only in late-stage tumours, whereas the telomerase RNA was present at higher than normal levels in pre-neoplastic stages and increased further in late-stage tumours. However, the RNA levels did not parallel the amounts of telomerase activity detected, suggesting that regulation of telomerase activity does not correlate with the regulation of its RNA component. These results establish a direct correlation between progression to late-stage tumours and induction of telomerase activity, and suggest that the initial upregulation of telomerase RNA is an early event. To address the role of telomerase during normal mouse development and tumour formation, we have constructed a knockout mouse for the mouse telomerase RNA, mTR-/-. These mice and the cell lines derived from them are telomerase deficient.

Published
1997

19. CELL BIOLOGY AND SIGNALING

Author

Furnari, F., primary, Fenton, T., additional, Nathanson, D., additional, de Alberquerque, C. P., additional, Kuga, D., additional, Wanami, A., additional, Dang, J., additional, Yang, H., additional, Tanaka, K., additional, Gao, L., additional, Oba-Shinjo, S., additional, Uno, M., additional, Inda, M.-d.-M., additional, Bachoo, R., additional, James, C. D., additional, DePinho, R., additional, Vandenberg, S., additional, Zhou, H., additional, Marie, S., additional, Mischel, P., additional, Cavenee, W., additional, Szerlip, N., additional, Pedraza, A., additional, Huse, J., additional, Mikkelsen, T., additional, Brennan, C., additional, Castellani, R. J., additional, Ivanova, S., additional, Gerzanich, V. V., additional, Simard, J. M., additional, Ito, M., additional, See, W., additional, Mukherjee, J., additional, Ohba, S., additional, Tan, I.-L., additional, Pieper, R. O., additional, Lukiw, W. J., additional, Culicchia, F., additional, Pogue, A., additional, Bhattacharjee, S., additional, Zhao, Y., additional, Proescholdt, M. A., additional, Merrill, M., additional, Storr, E. M., additional, Lohmeier, A., additional, Brawanski, A., additional, Abraham, S., additional, Jensen, R., additional, Khatua, S., additional, Gopal, U., additional, Du, J., additional, He, F., additional, Golub, T., additional, Isaacs, J. S., additional, Dietrich, J., additional, Kalogirou-Valtis, Y., additional, Ly, I., additional, Scadden, D., additional, Proschel, C., additional, Mayer-Proschel, M., additional, Rempel, S. A., additional, Schultz, C. R., additional, Golembieski, W., additional, Brodie, C., additional, Mathew, L. K., additional, Skuli, N., additional, Mucaj, V., additional, Imtiyaz, H. Z., additional, Venneti, S., additional, Lal, P., additional, Zhang, Z., additional, Davuluri, R. V., additional, Koch, C., additional, Evans, S., additional, Simon, M. C., additional, Ranganathan, P., additional, Clark, P., additional, Salamat, S., additional, Kuo, J. S., additional, Kalejta, R. F., additional, Bhattacharjee, B., additional, Renzette, N., additional, Moser, R. P., additional, Kowalik, T. F., additional, McFarland, B. C., additional, Ma, J.-Y., additional, Langford, C. P., additional, Gillespie, G. Y., additional, Yu, H., additional, Zheng, Y., additional, Nozell, S. E., additional, Huszar, D., additional, Benveniste, E. N., additional, Lawrence, J. E., additional, Cook, N. J., additional, Rovin, R. A., additional, Winn, R. J., additional, Godlewski, J. A., additional, Ogawa, D., additional, Bronisz, A., additional, Lawler, S., additional, Chiocca, E. A., additional, Lee, S. X., additional, Wong, E. T., additional, Swanson, K. D., additional, Liu, K.-w., additional, Feng, H., additional, Kazlauskas, A., additional, Smith, E. M., additional, Symes, K., additional, Hamilton, R. L., additional, Nagane, M., additional, Nishikawa, R., additional, Hu, B., additional, Cheng, S.-Y., additional, Silber, J., additional, Jacobsen, A., additional, Ozawa, T., additional, Harinath, G., additional, Brennan, C. W., additional, Holland, E. C., additional, Sander, C., additional, Huse, J. T., additional, Sengupta, R., additional, Dubuc, A., additional, Ward, S., additional, Yang, L., additional, Northcott, P., additional, Kroll, K., additional, Taylor, M., additional, Wechsler-Reya, R., additional, Rubin, J., additional, Chu, W.-T., additional, Lee, H.-T., additional, Huang, F.-J., additional, Aldape, K., additional, Yao, J., additional, Steeg, P. S., additional, Lu, Z., additional, Xie, K., additional, Huang, S., additional, Sim, H., additional, Agudelo-Garcia, P. A., additional, Viapiano, M. S., additional, Saldivar, J., additional, Dolan, C., additional, Mora, M., additional, Nuovo, G., additional, Cole, S., additional, Stegh, A. H., additional, Ryu, M.-J., additional, Liu, Y., additional, Zhong, X., additional, Marwaha, S., additional, Li, H., additional, Wang, J., additional, Chang, Q., additional, Zhang, J., additional, Ng, H.-K., additional, Poon, W. S., additional, Zhou, L., additional, Pang, J. C., additional, Chan, A., additional, Didier, S., additional, Kwiatkowska, A., additional, Ennis, M., additional, Fortin, S., additional, Rushing, E., additional, Eschbacher, J., additional, Tran, N., additional, Symons, M., additional, Roldan, G., additional, McIntyre, J. B., additional, Easaw, J., additional, Magliocco, A., additional, Wykosky, J., additional, Furnari, F., additional, Lu, D., additional, Mreich, E., additional, Chung, S., additional, Teo, C., additional, Wheeler, H., additional, McDonald, K. L., additional, Lawn, S., additional, Forsyth, P., additional, Sonabend, A. M., additional, Lei, L., additional, Kennedy, B., additional, Soderquist, C., additional, Guarnieri, P., additional, Leung, R., additional, Yun, J., additional, Sisti, J., additional, Castelli, M., additional, Bruce, S., additional, Bruce, R., additional, Ludwig, T., additional, Rosenfeld, S., additional, Bruce, J. N., additional, Canoll, P., additional, Lamszus, K., additional, Schulte, A., additional, Gunther, H. S., additional, Riethdorf, S., additional, Phillips, H. S., additional, Westphal, M., additional, Siegal, T., additional, Zrihan, D., additional, Granit, A., additional, Lavon, I., additional, Singh, M., additional, Chandra, J., additional, Nakashima, H., additional, Godlewski, J., additional, Chiocca, A. E., additional, Kapoor, G. S., additional, Poptani, H., additional, Ittyerah, R., additional, O'Rourke, D. M., additional, Sadraei, N. H., additional, Burgett, M., additional, Ahluwalia, M., additional, Tipps, R., additional, Khosla, D., additional, Weil, R., additional, Nowacki, A., additional, Prayson, R., additional, Shi, T., additional, Gladson, C., additional, Moeckel, S., additional, Meyer, K., additional, Bosserhoff, A., additional, Spang, R., additional, Leukel, P., additional, Vollmann, A., additional, Jachnick, B., additional, Stangl, C., additional, Proescholdt, M., additional, Bogdahn, U., additional, Hau, P., additional, Kaur, G., additional, Sun, M., additional, Kaur, R., additional, Bloch, O., additional, Jian, B., additional, Parsa, A. T., additional, Hossain, A., additional, Shinojima, N., additional, Gumin, J., additional, Feng, G., additional, Lang, F. F., additional, Li, L., additional, Yang, C.-R., additional, Chakraborty, S., additional, Hatanpaa, K., additional, Chauncey, S., additional, Jiwani, A., additional, Habib, A., additional, Nguyen, T., additional, Munson, J., additional, Machaidze, R., additional, Kaluzova, M., additional, Bellamkonda, R., additional, Hadjipanayis, C. G., additional, Zhang, Y., additional, McFarland, B., additional, Bredel, M., additional, Lee, S.-H., additional, Zerrouqi, A., additional, Khwaja, F., additional, Devi, N. S., additional, Van Meir, E. G., additional, Haseley, A., additional, Boone, S., additional, Wojton, J., additional, Yu, L., additional, Kaur, B., additional, Wojton, J. A., additional, Naduparambil, J., additional, Denton, N., additional, Chakravarti, A., additional, Conrad, C. A., additional, Wang, X., additional, Sheng, X., additional, Nilsson, C., additional, Marshall, A. G., additional, Emmett, M. R., additional, Hu, Y., additional, Mark, L., additional, Zhou, Y.-H. Z., additional, Dhruv, H., additional, McDonough, W., additional, Armstrong, B., additional, Tuncali, S., additional, Kislin, K., additional, Berens, M., additional, Plas, D., additional, Gallo, C., additional, Stringer, K., additional, Kendler, A., additional, McPherson, C., additional, Castelli, M. A., additional, Ellis, J. A., additional, Assanah, M., additional, Ogden, A., additional, Liang, J., additional, Piao, Y., additional, deGroot, J. F., additional, Gordon, N., additional, Patel, D., additional, Palanichamy, K., additional, Hervey-Jumper, S., additional, Wang, A., additional, He, X., additional, Zhu, T., additional, Heth, J., additional, Muraszko, K., additional, Fan, X., additional, Liu, W. M., additional, Huang, P., additional, Rani, S., additional, Stettner, M. R., additional, Jerry, S., additional, Dai, Q., additional, Kappes, J., additional, Gladson, C. L., additional, Chakravarty, D., additional, Koul, D., additional, Alfred Yung, W. K., additional, Jensen, S. A., additional, Luciano, J., additional, Calvert, A., additional, Nagpal, V., additional, Stegh, A., additional, Kang, S.-H., additional, Yu, M. O., additional, Lee, M.-G., additional, Chi, S.-G., additional, Chung, Y.-G., additional, Cooper, M. K., additional, Valadez, J. G., additional, Grover, V. K., additional, Kouri, F. M., additional, Chin, L., additional, Ahluwalia, M. S., additional, Weil, R. J., additional, McGraw, M., additional, Barnett, G. H., additional, Kang, C., additional, Zou, J., additional, Lan, F., additional, Yue, X., additional, Shi, Z., additional, Zhang, K., additional, Han, L., additional, Pu, P., additional, Seaman, B. F., additional, Tran, N. D., additional, Battiste, J. D., additional, Sirasanagandla, S., additional, Maher, E. A., additional, Sugiarto, S., additional, Persson, A., additional, Munoz, E. G., additional, Waldhuber, M., additional, Stallcup, W., additional, Philips, J., additional, Berger, M. S., additional, Bergers, G., additional, Weiss, W. A., additional, and Petritsch, C., additional

Published
2011
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22. Cell Biology and Signaling

Author

Long, P. M., primary, Wesley, U. V., additional, Jaworski, D. M., additional, Rana, M., additional, Kiehl, T.-R., additional, So, K., additional, Gould, P., additional, Ajewung, N., additional, Kamnasaran, D., additional, Emmett, M. R., additional, Wang, X., additional, Marshall, A. G., additional, Ji, Y., additional, Fokt, I., additional, Skora, S., additional, Conrad, C. A., additional, Priebe, W., additional, Zhu, H., additional, Cao, X., additional, Keir, S., additional, Ali-Osman, F., additional, Lo, H.-W., additional, Da Fonseca, C. O., additional, Arun, V., additional, Wiley, J. C., additional, Kaur, H., additional, Guha, A., additional, Fenton, K., additional, Abdelwahab, M. G., additional, Stafford, P., additional, Rho, J. M., additional, Preul, M. C., additional, Scheck, A. C., additional, Brossier, N. M., additional, Carroll, S. L., additional, Gajadhar, A., additional, Mukherjee, J., additional, Wolf, A., additional, Hawkins, C., additional, Costa, P., additional, Cardoso, A. L. C., additional, de Almeida, L. P., additional, de Lima, M. C. P., additional, Canoll, P., additional, Bruce, J., additional, Lavon, I., additional, Granit, A., additional, Einstein, O., additional, Ben-Hur, T., additional, Siegal, T., additional, Pang, J. C., additional, Poon, W. S., additional, Zhou, L., additional, Ng, H.-K., additional, Rovin, R. A., additional, Lawrence, J. E., additional, Segula, J. J., additional, Winn, R. J., additional, Patil, S., additional, Burzynski, S. R., additional, Mrowczynski, E., additional, Grela, K., additional, Cheng, S., additional, Liu, K., additional, Feng, H., additional, Bacho, R., additional, Kazlauskas, A., additional, Smith, E. M., additional, Symes, K., additional, Hu, B., additional, Lee, C. Y., additional, Fotovati, A., additional, Dunn, S. E., additional, Proescholdt, M. A., additional, Storr, E.-M., additional, Lohmeier, A., additional, Brawanski, A., additional, Jarzynka, M. J., additional, Ravichandran, K. S., additional, Vuori, K., additional, Tang, C., additional, Nshikawa, R., additional, Johns, T. G., additional, Furnari, F. B., additional, Cavenee, W. K., additional, Zhong, J., additional, O'Neill, G. M., additional, Deleyrolle, L. P., additional, Rahman, M., additional, Dunbar, E. M., additional, Caldeira, M. A., additional, Reynolds, B. A., additional, Liu, X., additional, Yacyshyn, S., additional, Dasgupta, B., additional, Han, X., additional, Yang, X., additional, Wheeler, C. G., additional, Filippova, N., additional, Langford, C. P., additional, Ding, Q., additional, Fathallah, H. M., additional, Gillespie, G. Y., additional, Nabors, L. B., additional, Davidson, T. B., additional, Gortalum, F., additional, Ji, L., additional, Engell, K., additional, Sposto, R., additional, Asgharzadeh, S., additional, Erdreich-Epstein, A., additional, Lawn, S. O., additional, Weiss, S., additional, Senger, D., additional, Forsyth, P., additional, Latha, K., additional, Chumbalkar, V., additional, Li, M., additional, Gururaj, A., additional, Hwang, Y., additional, Maywald, R., additional, Dakeng, S., additional, Dao, L., additional, Baggerly, K., additional, Sawaya, R., additional, Aldape, K., additional, Cavenee, W., additional, Furnari, F., additional, Bogler, O., additional, Arumugam, J., additional, Sim, H., additional, Pineda, C. A., additional, Pan, Y., additional, Viapiano, M. S., additional, Van Schaick, J. A., additional, Akagi, K., additional, Burkett, S., additional, DiFabio, C., additional, Tuskan, R., additional, Walrath, J., additional, Reilly, K., additional, Dai, B., additional, Jing, Z., additional, Kang, S.-H., additional, Li, D., additional, Xie, K., additional, Huang, S., additional, Gong, X., additional, Vuong, Y., additional, Bota, D. A., additional, Stegh, A. H., additional, Inda, M.-d.-M., additional, Bonavia, R., additional, Mukasa, A., additional, Narita, Y., additional, Sah, D., additional, Vandenberg, S., additional, Brennan, C., additional, Johns, T., additional, Bachoo, R., additional, Hadwiger, P., additional, Tan, P., additional, DePinho, R., additional, Kusne, Y., additional, Meerson, A., additional, Rushing, E. J., additional, Yang, W., additional, McDonough, W., additional, Kislin, K., additional, Loftus, J. C., additional, Berens, M., additional, Lu, Z., additional, Ghosh, S., additional, Verma, A., additional, Zhou, H., additional, Chin, S., additional, Bruggers, C., additional, Kestle, J., additional, Khatua, S., additional, Broekman, M. L., additional, Maas, N. S., additional, Skog, J., additional, Breakefield, X. O., additional, Sena-Esteves, M., additional, de Vrij, J., additional, Lamfers, M., additional, Maas, N., additional, Dirven, C., additional, Esteves, M., additional, Broekman, M., additional, Chidambaram, A., additional, Dumur, C. I., additional, Graf, M., additional, Vanmeter, T. E., additional, Fillmore, H. L., additional, Broaddus, W. C., additional, Silber, J., additional, Ozawa, T., additional, Kastenhuber, E., additional, Djaballah, H., additional, Holland, E. C., additional, Huse, J. T., additional, Agnihotri, S., additional, Munoz, D., additional, Han, J. E., additional, Albesiano, E., additional, Pradilla, G., additional, Lim, M., additional, Alshami, J., additional, Sabau, C., additional, Seyed Sadr, M., additional, Anan, M., additional, Seyed Sadr, E., additional, Siu, V., additional, Del Maestro, R., additional, Trinh, G., additional, Le, P., additional, Petrecca, K., additional, Sonabend, A. M., additional, Soderquist, C., additional, Lei, L., additional, Guarnieri, P., additional, Leung, R., additional, Yun, J., additional, Sisti, J., additional, Castelli, M., additional, Bruce, S., additional, Bruce, R., additional, Ludwig, T., additional, Rosenfeld, S., additional, Bruce, J. N., additional, Phillips, J. J., additional, Huillard, E., additional, Polley, M.-Y., additional, Rosen, S. D., additional, Rowitch, D. H., additional, Werb, Z., additional, Sarkar, C., additional, Jha, P., additional, Pathak, P., additional, Suri, V., additional, Sharma, M. C., additional, Chattopadhyay, P., additional, Chosdol, K., additional, Suri, A., additional, Gupta, D., additional, Mahapatra, A. K., additional, Kapoor, G. S., additional, Zhan, Y., additional, Boockvar, J. A., additional, O'Rourke, D. M., additional, Kwatra, M. M., additional, Kim, J. W., additional, Park, C.-K., additional, Han, J. H., additional, Park, S. H., additional, Kim, S.-K., additional, Jung, H.-W., additional, Narayanan, R., additional, Levin, B. S., additional, Maeder, M. L., additional, Joung, J. K., additional, Nutt, C. L., additional, Louis, D. N., additional, Dudley, A., additional, Jayaram, P., additional, Pei, Z., additional, Shi, X., additional, Laterra, J., additional, Watkins, P. A., additional, Mawrin, C., additional, Rempel, S. A., additional, McClung, H. M., additional, McFarland, B. C., additional, Nozell, S. E., additional, Huszar, D., additional, Benveniste, E. N., additional, Burton, T., additional, Eisenstat, D. D., additional, Gibson, S. 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Published
2010
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38. Somatic p16INK4a loss accelerates melanomagenesis.

Author

Monahan, K B, Rozenberg, G I, Krishnamurthy, J, Johnson, S M, Liu, W, Bradford, M K, Horner, J, DePinho, R A, and Sharpless, N E

Subjects
TUMOR suppressor proteins, MELANOMA, MELANOCYTES, ANTINEOPLASTIC agents, TRANSGENIC mice, P53 antioncogene, CELLULAR signal transduction
Abstract

Loss of p16INK4a-RB and ARF-p53 tumor suppressor pathways, as well as activation of RAS-RAF signaling, is seen in a majority of human melanomas. Although heterozygous germline mutations of p16INK4a are associated with familial melanoma, most melanomas result from somatic genetic events: often p16INK4a loss and N-RAS or B-RAF mutational activation, with a minority possessing alternative genetic alterations such as activating mutations in K-RAS and/or p53 inactivation. To generate a murine model of melanoma featuring some of these somatic genetic events, we engineered a novel conditional p16INK4a-null allele and combined this allele with a melanocyte-specific, inducible CRE recombinase strain, a conditional p53-null allele and a loxP-stop-loxP activatable oncogenic K-Ras allele. We found potent synergy between melanocyte-specific activation of K-Ras and loss of p16INK4a and/or p53 in melanomagenesis. Mice harboring melanocyte-specific activated K-Ras and loss of p16INK4a and/or p53 developed invasive, unpigmented and nonmetastatic melanomas with short latency and high penetrance. In addition, the capacity of these somatic genetic events to rapidly induce melanomas in adult mice suggests that melanocytes remain susceptible to transformation throughout adulthood. [ABSTRACT FROM AUTHOR]

Published
2010
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45. Telomere dysfunction triggers developmentally regulated germ cell apoptosis.

Author

T, Hemann M, L, Rudolph K, A, Strong M, A, DePinho R, L, Chin, and W, Greider C

Abstract

Telomere dysfunction results in fertility defects in a number of organisms. Although data from fission yeast and Caenorhabditis elegans suggests that telomere dysfunction manifests itself primarily as defects in proper meiotic chromosome segregation, it is unclear how mammalian telomere dysfunction results in germ cell death. To investigate the specific effects of telomere dysfunction on mammalian germ cell development, we examined the meiotic progression and germ cell apoptosis in late generation telomerase null mice. Our results indicate that chromosome asynapsis and missegregation are not the cause of infertility in mice with shortened telomeres. Rather, telomere dysfunction is recognized at the onset of meiosis, and cells with telomeric defects are removed from the germ cell precursor pool. This germ cell telomere surveillance may be an important mechanism to protect against the transmission of dysfunctional telomeres and chromosomal abnormalities.

Published
2001

47. Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression.

Author

O'Hagan, R C, Ohh, M, David, G, de Alboran, I M, Alt, F W, Kaelin, W G, and DePinho, R A

Abstract

The c-Myc oncoprotein plays an important role in the growth and proliferation of normal and neoplastic cells. To execute these actions, c-Myc is thought to regulate functionally diverse sets of genes that directly govern cellular mass and progression through critical cell cycle transitions. Here, we provide several lines of evidence that c-Myc promotes ubiquitin-dependent proteolysis by directly activating expression of the Cul1 gene, encoding a critical component of the ubiquitin ligase SCF(SKP2). The cell cycle inhibitor p27(kip1) is a known target of the SCF(SKP2) complex, and Myc-induced Cul1 expression matched well with the kinetics of declining p27(kip1) protein. Enforced Cul1 expression or antisense neutralization of p27(kip1) was capable of overcoming the slow-growth phenotype of c-Myc null primary mouse embryonic fibroblasts (MEFs). In reconstitution assays, the addition of in vitro translated Cul1 protein alone was able to restore p27(kip1) ubiquitination and degradation in lysates derived from c-myc(-/-) MEFs or density-arrested human fibroblasts. These functional and biochemical data provide a direct link between c-Myc transcriptional regulation and ubiquitin-mediated proteolysis and together support the view that c-Myc promotes G(1) exit in part via Cul1-dependent ubiquitination and degradation of the CDK inhibitor, p27(kip1).

Published
2000

48. N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation.

Author

Malynn, B A, de Alboran, I M, O'Hagan, R C, Bronson, R, Davidson, L, DePinho, R A, and Alt, F W

Abstract

Members of the myc family of cellular oncogenes have been implicated as transcriptional regulators in pathways that govern cellular proliferation and death. In addition, N-myc and c-myc are essential for completion of murine embryonic development. However, the basis for the evolutionary conservation of myc gene family has remained unclear. To elucidate this issue, we have generated mice in which the endogenous c-myc coding sequences have been replaced with N-myc coding sequences. Strikingly, mice homozygous for this replacement mutation can survive into adulthood and reproduce. Moreover, when expressed from the c-myc locus, N-myc is similarly regulated and functionally complementary to c-myc in the context of various cellular growth and differentiation processes. Therefore, the myc gene family must have evolved, to a large extent, to facilitate differential patterns of expression.

Published
2000

49. Essential role for Max in early embryonic growth and development.

Author

Shen-Li, H, O'Hagan, R C, Hou, H, Horner, J W, Lee, H W, and DePinho, R A

Abstract

Loss of Max function in the mouse resulted in generalized developmental arrest of both embryonic and extraembryonic tissues at early postimplantation (approximately E5.5-6.5), coincident with loss or dilution of maternal Max stores in the expanding embryo in vivo and in blastocyst outgrowths in vitro. Developmentally arrested embryos were reduced in size and exhibited widespread cytological degeneration and feeble BrdU incorporation. Max and, by extension, the Myc superfamily, serve essential roles in early mammalian development and a maternal reservoir of Max exists in sufficient amount to sustain Myc superfamily function through preimplantation stages of development.

Published
2000

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