![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Research Papers
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27299, USA.
Abstract
The p53 gene is the most frequent target of structural and functional genetic mutations in human cancer. Thus, considerable effort has been devoted to mapping the functional domains of p53 with regard to their impact on tumorigenesis in vivo. Studies have shown that the carboxy-terminal domain of p53 is sufficient for transformation in vitro. To determine whether a transdominant-negative p53 protein could be used to elicit a tissue-specific p53-null effect in vivo, we tested whether a carboxy-terminal p53 fragment (amino acids 302-390) could abolish p53-dependent apoptosis in an established tumor progression model. We showed previously that loss of p53-dependent apoptosis accelerates brain tumorigenesis in a transgenic mouse model. Here, we show that the same effect can be elicited by expressing a dominant-negative p53 protein tissue specifically in the presence of wild-type p53. Transgenic mice in which pRb function has been disrupted and that coexpress a p53 carboxy-terminal dominant-negative fragment (p53DD) develop aggressive brain tumors mimicking genetic loss of p53 in this model. Inactivation of endogenous p53, which we show to be complexed with p53DD, results in a reduction in apoptosis and acceleration of tumorigenesis. These studies establish a mechanism for tissue-specific knock out of p53 function in vivo.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  T.-K. Kim, J.-S. Lee, S.-Y. Oh, X. Jin, Y.-J. Choi, T.-H. Lee, E. h. Lee, Y.-K. Choi, S. You, Y. G. Chung, et al. Direct Transcriptional Activation of Promyelocytic Leukemia Protein by IFN Regulatory Factor 3 Induces the p53-Dependent Growth Inhibition of Cancer Cells Cancer Res., December 1, 2007; 67(23): 11133 - 11140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Garner, F. Martinon, J. Tschopp, P. Beard, and K. Raj Cells with Defective p53-p21-pRb Pathway Are Susceptible to Apoptosis Induced by p84N5 via Caspase-6 Cancer Res., August 15, 2007; 67(16): 7631 - 7637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. DeYoung, C. M. Johannessen, C.-O. Leong, W. Faquin, J. W. Rocco, and L. W. Ellisen Tumor-Specific p73 Up-regulation Mediates p63 Dependence in Squamous Cell Carcinoma Cancer Res., October 1, 2006; 66(19): 9362 - 9368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Abate-Shen A new generation of mouse models of cancer for translational research. Clin. Cancer Res., September 15, 2006; 12(18): 5274 - 5276. [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Yeh, B. O. Lew, and A. R. Means The Loss of PIN1 Deregulates Cyclin E and Sensitizes Mouse Embryo Fibroblasts to Genomic Instability J. Biol. Chem., January 6, 2006; 281(1): 241 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Markovics, P. A. Carroll, M. T. S. Robles, H. Pope, C. M. Coopersmith, and J. M. Pipas Intestinal Dysplasia Induced by Simian Virus 40 T Antigen Is Independent of p53 J. Virol., June 15, 2005; 79(12): 7492 - 7502. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-M. Tchou-Wong, Y. Jiang, H. Yee, J. LaRosa, T. C. Lee, A. Pellicer, J. Jagirdar, T. Gordon, J. D. Goldberg, and W. N. Rom Lung-Specific Expression of Dominant-Negative Mutant p53 in Transgenic Mice Increases Spontaneous and Benzo(a)pyrene-Induced Lung Cancer Am. J. Respir. Cell Mol. Biol., August 1, 2002; 27(2): 186 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Scott, M. O'Sullivan, S. Hafizi, L. M. Shapiro, and M. R. Bennett Human Vascular Smooth Muscle Cells From Restenosis or In-Stent Stenosis Sites Demonstrate Enhanced Responses to p53: Implications for Brachytherapy and Drug Treatment for Restenosis Circ. Res., March 8, 2002; 90(4): 398 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. DONAHUE, M. RAZMARA, J. B. HOEK, and T. B. KNUDSEN Direct influence of the p53 tumor suppressor on mitochondrial biogenesis and function FASEB J, March 1, 2001; 15(3): 635 - 644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. d. L. Coste, A. Mignon, M. Fabre, E. Gilbert, A. Porteu, T. V. Dyke, A. Kahn, and C. Perret Paradoxical Inhibition of c-myc-induced Carcinogenesis by Bcl-2 in Transgenic Mice Cancer Res., October 1, 1999; 59(19): 5017 - 5022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Slinskey, D. Barnes, and J. M. Pipas Simian Virus 40 Large T Antigen J Domain and Rb-Binding Motif Are Sufficient To Block Apoptosis Induced by Growth Factor Withdrawal in a Neural Stem Cell Line J. Virol., August 1, 1999; 73(8): 6791 - 6799. [Abstract] [Full Text]
|
|
|
|
 |
|
 V Gottifredi, A Peschiaroli, G. Fimia, and R Maione p53-independent apoptosis induced by muscle differentiation stimuli in polyomavirus large T-expressing myoblasts J. Cell Sci., January 7, 1999; 112(14): 2397 - 2407. [Abstract] [PDF]
|
|
|
|
 |
|
 E. Robanus-Maandag, M. Dekker, M. van der Valk, M.-L. Carrozza, J.-C. Jeanny, J.-H. Dannenberg, A. Berns, and H. te Riele p107 is a suppressor of retinoblastoma development in pRb-deficient mice Genes & Dev., June 1, 1998; 12(11): 1599 - 1609. [Abstract] [Full Text]
|
|
|
|
|
|
M. R. Bennett, T. D. Littlewood, S. M. Schwartz, and P. L. Weissberg Increased Sensitivity of Human Vascular Smooth Muscle Cells From Atherosclerotic Plaques to p53-Mediated Apoptosis Circ. Res., October 19, 1997; 81(4): 591 - 599. [Abstract] [Full Text]
|
|
|
|
|
|
S. Scott, M. O'Sullivan, S. Hafizi, L. M. Shapiro, and M. R. Bennett Human Vascular Smooth Muscle Cells From Restenosis or In-Stent Stenosis Sites Demonstrate Enhanced Responses to p53: Implications for Brachytherapy and Drug Treatment for Restenosis Circ. Res., March 8, 2002; 90(4): 398 - 404. [Abstract] [Full Text] [PDF]
|
|
