A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility
Jennifer L. Shepard, James F. Amatruda, Howard M. Stern, Aravind Subramanian, David Finkelstein, James Ziai, K. Rose Finley, Kathleen L. Pfaff, Candace Hersey, Yi Zhou, Bruce Barut, Matthew Freedman, Charles Lee, Jan Spitsbergen, Donna Neuberg, Gerhard Weber, Todd R. Golub, Jonathan N. Glickman, Jeffery L. Kutok, Jon C. AsterLeonard I. Zon
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Int Med - Chairman's Office
A major goal of cancer research has been to identify genes that contribute to cancer formation. The similar pathology between zebrafish and human tumors, as well as the past success of large-scale genetic screens in uncovering human disease genes, makes zebrafish an ideal system in which to find such new genes. Here, we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), that represents a loss-of-function mutation in bmyb, a transcriptional regulator and member of a putative protooncogene family, crb mutant embryos have defects in mitotic progression and spindle formation, and exhibit genome instability. Regulation of cyclin B levels by bmyb appears to be the mechanism of mitotic accumulation in crb. Carcinogenesis studies reveal increased cancer susceptibility in adult crb heterozygotes. Gene-expression signatures associated with loss of bmyb in zebrafish are also correlated with conserved signatures in human tumor samples, and down-regulation of the B-myb signature genes is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and demonstrate that loss of function of bmyb is associated with cancer.
https://doi.org/10.1073/pnas.0506583102
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Genomic Instability Medicine & Life Sciences 100%
Zebrafish Medicine & Life Sciences 92%
myb Genes Medicine & Life Sciences 20%
Cyclin B Medicine & Life Sciences 18%
Spindle Apparatus Medicine & Life Sciences 16%
Shepard, J. L., Amatruda, J. F., Stern, H. M., Subramanian, A., Finkelstein, D., Ziai, J., Finley, K. R., Pfaff, K. L., Hersey, C., Zhou, Y., Barut, B., Freedman, M., Lee, C., Spitsbergen, J., Neuberg, D., Weber, G., Golub, T. R., Glickman, J. N., Kutok, J. L., ... Zon, L. I. (2005). A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility. Proceedings of the National Academy of Sciences of the United States of America, 102(37), 13194-13199. https://doi.org/10.1073/pnas.0506583102
A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility. / Shepard, Jennifer L.; Amatruda, James F.; Stern, Howard M. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 37, 13.09.2005, p. 13194-13199.
Shepard, JL, Amatruda, JF, Stern, HM, Subramanian, A, Finkelstein, D, Ziai, J, Finley, KR, Pfaff, KL, Hersey, C, Zhou, Y, Barut, B, Freedman, M, Lee, C, Spitsbergen, J, Neuberg, D, Weber, G, Golub, TR, Glickman, JN, Kutok, JL, Aster, JC & Zon, LI 2005, 'A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 37, pp. 13194-13199. https://doi.org/10.1073/pnas.0506583102
Shepard JL, Amatruda JF, Stern HM, Subramanian A, Finkelstein D, Ziai J et al. A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility. Proceedings of the National Academy of Sciences of the United States of America. 2005 Sep 13;102(37):13194-13199. doi: 10.1073/pnas.0506583102
Shepard, Jennifer L. ; Amatruda, James F. ; Stern, Howard M. et al. / A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 37. pp. 13194-13199.
@article{b9ec028a61ed4336bd4e8d8cba4c8567,
title = "A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility",
abstract = "A major goal of cancer research has been to identify genes that contribute to cancer formation. The similar pathology between zebrafish and human tumors, as well as the past success of large-scale genetic screens in uncovering human disease genes, makes zebrafish an ideal system in which to find such new genes. Here, we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), that represents a loss-of-function mutation in bmyb, a transcriptional regulator and member of a putative protooncogene family, crb mutant embryos have defects in mitotic progression and spindle formation, and exhibit genome instability. Regulation of cyclin B levels by bmyb appears to be the mechanism of mitotic accumulation in crb. Carcinogenesis studies reveal increased cancer susceptibility in adult crb heterozygotes. Gene-expression signatures associated with loss of bmyb in zebrafish are also correlated with conserved signatures in human tumor samples, and down-regulation of the B-myb signature genes is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and demonstrate that loss of function of bmyb is associated with cancer.",
keywords = "Cell cycle",
author = "Shepard, {Jennifer L.} and Amatruda, {James F.} and Stern, {Howard M.} and Aravind Subramanian and David Finkelstein and James Ziai and Finley, {K. Rose} and Pfaff, {Kathleen L.} and Candace Hersey and Yi Zhou and Bruce Barut and Matthew Freedman and Charles Lee and Jan Spitsbergen and Donna Neuberg and Gerhard Weber and Golub, {Todd R.} and Glickman, {Jonathan N.} and Kutok, {Jeffery L.} and Aster, {Jon C.} and Zon, {Leonard I.}",
doi = "10.1073/pnas.0506583102",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
publisher = "National Academy of Sciences",
T1 - A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility
AU - Shepard, Jennifer L.
AU - Amatruda, James F.
AU - Stern, Howard M.
AU - Subramanian, Aravind
AU - Finkelstein, David
AU - Ziai, James
AU - Finley, K. Rose
AU - Pfaff, Kathleen L.
AU - Hersey, Candace
AU - Zhou, Yi
AU - Barut, Bruce
AU - Freedman, Matthew
AU - Lee, Charles
AU - Spitsbergen, Jan
AU - Neuberg, Donna
AU - Weber, Gerhard
AU - Golub, Todd R.
AU - Glickman, Jonathan N.
AU - Kutok, Jeffery L.
AU - Aster, Jon C.
AU - Zon, Leonard I.
N2 - A major goal of cancer research has been to identify genes that contribute to cancer formation. The similar pathology between zebrafish and human tumors, as well as the past success of large-scale genetic screens in uncovering human disease genes, makes zebrafish an ideal system in which to find such new genes. Here, we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), that represents a loss-of-function mutation in bmyb, a transcriptional regulator and member of a putative protooncogene family, crb mutant embryos have defects in mitotic progression and spindle formation, and exhibit genome instability. Regulation of cyclin B levels by bmyb appears to be the mechanism of mitotic accumulation in crb. Carcinogenesis studies reveal increased cancer susceptibility in adult crb heterozygotes. Gene-expression signatures associated with loss of bmyb in zebrafish are also correlated with conserved signatures in human tumor samples, and down-regulation of the B-myb signature genes is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and demonstrate that loss of function of bmyb is associated with cancer.
AB - A major goal of cancer research has been to identify genes that contribute to cancer formation. The similar pathology between zebrafish and human tumors, as well as the past success of large-scale genetic screens in uncovering human disease genes, makes zebrafish an ideal system in which to find such new genes. Here, we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), that represents a loss-of-function mutation in bmyb, a transcriptional regulator and member of a putative protooncogene family, crb mutant embryos have defects in mitotic progression and spindle formation, and exhibit genome instability. Regulation of cyclin B levels by bmyb appears to be the mechanism of mitotic accumulation in crb. Carcinogenesis studies reveal increased cancer susceptibility in adult crb heterozygotes. Gene-expression signatures associated with loss of bmyb in zebrafish are also correlated with conserved signatures in human tumor samples, and down-regulation of the B-myb signature genes is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and demonstrate that loss of function of bmyb is associated with cancer.
KW - Cell cycle
U2 - 10.1073/pnas.0506583102
DO - 10.1073/pnas.0506583102
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America