scholarly journals Skip interacts with the retinoblastoma tumor suppressor and inhibits its transcriptional repression activity

2002 ◽  
Vol 30 (23) ◽  
pp. 5261-5268 ◽  
Author(s):  
T. Prathapam
Keyword(s):  
Tumor Suppressor ◽  
Transcriptional Repression ◽  
Retinoblastoma Tumor Suppressor ◽  
Retinoblastoma Tumor

scholarly journals Retinoblastoma Tumor Suppressor: Analyses of Dynamic Behavior in Living Cells Reveal Multiple Modes of Regulation

2003 ◽  
Vol 23 (22) ◽  
pp. 8172-8188 ◽  
Author(s):  
Steven P. Angus ◽  
David A. Solomon ◽  
Lioba Kuschel ◽  
Robert F. Hennigan ◽  
Erik S. Knudsen
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Dynamic Behavior ◽  
Transcriptional Repression ◽  
Fluorescent Protein ◽  
Dynamic Equilibrium ◽  
Living Cells ◽  
Retinoblastoma Tumor Suppressor ◽  
Retinoblastoma Tumor

ABSTRACT The retinoblastoma tumor suppressor, RB, assembles multiprotein complexes to mediate cell cycle inhibition. Although many RB binding partners have been suggested to underlie these functions, the validity of these interactions on the behavior of RB complexes in living cells has not been investigated. Here, we studied the dynamic behavior of RB by using green fluorescent protein-RB fusion proteins. Although these proteins were universally nuclear, phosphorylation or oncoprotein binding mediated their active exclusion from the nucleolus. In vivo imaging approaches revealed that RB exists in dynamic equilibrium between a highly mobile and a slower diffusing species, and genetic lesions associated with tumorigenesis increased the fraction of RB in a highly mobile state. The RB complexes dictating cell cycle arrest were surprisingly dynamic and harbored a relatively short residence time on chromatin. In contrast, this rapid exchange was attenuated in cells that are hypersensitive to RB, suggesting that responsiveness may inversely correlate with mobility. The stability of RB dynamics within the cell was additionally modified by the presence and function of critical corepressors. Last, the RB-assembled complexes present in living cells were primarily associated with E2F binding sites in chromatin. In contrast to RB, E2F1 consistently maintained a stable association with E2F sites regardless of cell type. Together, these results elucidate the kinetic framework of RB tumor suppressor action in transcriptional repression and cell cycle regulation.

scholarly journals Degradation of the Retinoblastoma Tumor Suppressor by the Human Papillomavirus Type 16 E7 Oncoprotein Is Important for Functional Inactivation and Is Separable from Proteasomal Degradation of E7

2001 ◽  
Vol 75 (16) ◽  
pp. 7583-7591 ◽  
Author(s):  
Sonia L. Gonzalez ◽  
Matt Stremlau ◽  
Xi He ◽  
John R. Basile ◽  
Karl Münger
Keyword(s):  
Human Papillomavirus ◽  
Tumor Suppressor ◽  
Selection Process ◽  
State Level ◽  
Proteasomal Degradation ◽  
Biological Indicator ◽  
26S Proteasome ◽  
Amino Terminal ◽  
Retinoblastoma Tumor Suppressor ◽  
Retinoblastoma Tumor

ABSTRACT The steady-state level and metabolic half-life of retinoblastoma tumor suppressor protein pRB are decreased in cells that express high-risk human papillomavirus (HPV) E7 proteins. Here we show that pRB degradation is a direct activity of E7 and does not reflect a property of cell lines acquired during the selection process for E7 expression. An amino-terminal domain of E7 that does not directly contribute to pRB binding but is required for transformation is also necessary for E7-mediated pRB degradation. Treatment with inhibitors of the 26S proteasome not only blocks E7-mediated pRB degradation but also causes the stabilization of E7. Mutagenic analyses, however, reveal that the processes of proteasomal degradation of E7 and pRB are not linked processes. HPV type 16 E7 also targets the pRB-related proteins p107 and p130 for destabilization by a proteasome-dependent mechanism. Using the SAOS2 flat-cell assay as a biological indicator for pRB function, we demonstrate that pRB degradation, not solely binding, is important for the E7-induced inactivation of pRB.

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