TY - JOUR
T1 - p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis
AU - Chin, Lynda
AU - Artandi, Steven E.
AU - Shen, Qiong
AU - Tam, Alice
AU - Lee, Shwu Luan
AU - Gottlieb, Geoffrey J.
AU - Greider, Carol W.
AU - DePinho, Ronald A.
N1 - Funding Information:
We are grateful to J. Daley for technical advice on FACS and flow FISH analyses; K.-H. Lee for assistance with MEF isolation; and K. L. Rudolph for the gift of G4 mTR −/− MEFs. The authors thank M. Wong, C. Cohen, and J. Leung for technical assistance with mouse colony management; B. Furman, K. E. Cedeno-Baier, and L. Husted of Quest Diagnostics for tissue sample preparation; N. Schreiber-Agus, T. Raveh, and G. Merlino for critical reading of the manuscript; and members of the DePinho laboratory for helpful comments. This work was supported by grants from the NIH (R01HD34880 and R01HD28317) and an AHA grant-in-aid to R. A. D.; L. C. is supported by an NIH grant (K08AR02104–01). S. E. A. is supported by an NIH grant (5T32CA09172–24) and a Breast Cancer Research Grant Award from the Massachusetts Department of Public Health. A. T. is a Howard Hughes Medical Institute Medical Student Research Training Fellow. C. W. G. is supported by the NIH (CA16519). R. A. D. is an American Cancer Society Research Professor. Support from the DFCI Cancer Core grant to R. A .D. and L. C. is acknowledged.
PY - 1999/5/14
Y1 - 1999/5/14
N2 - Maintenance of telomere length and function is critical for the efficient proliferation of eukaryotic cells. Here, we examine the interactions between telomere dysfunction and p53 in cells and organs of telomerase-deficient mice. Coincident with severe telomere shortening and associated genomic instability, p53 is activated, leading to growth arrest and/or apoptosis. Deletion of p53 significantly attenuated the adverse cellular and organismal effects of telomere dysfunction, but only during the earliest stages of genetic crisis. Correspondingly, the loss of telomere function and p53 deficiency cooperated to initiate the transformation process. Together, these studies establish a key role for p53 in the cellular response to telomere dysfunction in both normal and neoplastic cells, question the significance of crisis as a tumor suppressor mechanism, and identify a biologically relevant stage of advanced crisis, termed genetic catastrophe.
AB - Maintenance of telomere length and function is critical for the efficient proliferation of eukaryotic cells. Here, we examine the interactions between telomere dysfunction and p53 in cells and organs of telomerase-deficient mice. Coincident with severe telomere shortening and associated genomic instability, p53 is activated, leading to growth arrest and/or apoptosis. Deletion of p53 significantly attenuated the adverse cellular and organismal effects of telomere dysfunction, but only during the earliest stages of genetic crisis. Correspondingly, the loss of telomere function and p53 deficiency cooperated to initiate the transformation process. Together, these studies establish a key role for p53 in the cellular response to telomere dysfunction in both normal and neoplastic cells, question the significance of crisis as a tumor suppressor mechanism, and identify a biologically relevant stage of advanced crisis, termed genetic catastrophe.
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U2 - 10.1016/S0092-8674(00)80762-X
DO - 10.1016/S0092-8674(00)80762-X
M3 - Article
C2 - 10338216
AN - SCOPUS:0033553516
SN - 0092-8674
VL - 97
SP - 527
EP - 538
JO - Cell
JF - Cell
IS - 4
ER -