scholarly journals mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein.

1996 ◽  
Vol 16 (5) ◽  
pp. 2445-2452 ◽  
Author(s):  
J Chen ◽  
X Wu ◽  
J Lin ◽  
A J Levine
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Biological Activities ◽  
Tumor Suppressor Protein ◽  
G1 Arrest ◽  
Physical Interaction ◽  
P53 Tumor Suppressor ◽  
Cycle Arrest ◽  
P53 Tumor Suppressor Protein

The mdm-2 gene encodes a 90-kDa polypeptide that binds specifically to the p53 tumor suppressor protein. This physical interaction results in the inhibition of the transcriptional functions of p53 (J. Chen, J. Lin, and A. J. Levine, Mol. Med. 1:142-152, 1995, and J. Momand, G. P. Zambetti, D. C. Olson, D. George, and A. J. Levine, Cell 69:1237-1245, 1992). Experiments are described that demonstrate the ability of mdm-2 to abrogate both the p53-mediated cell cycle arrest and the apoptosis functions. In addition, the results presented here suggest that mdm-2 binding to p53 and the resultant inhibition of p53 transcription functions are critical for reversing p53-mediated cell cycle arrest. The N-terminal half or domain of the mdm-2 protein is sufficient to regulate these biological activities of p53, consistent with the possibility that the highly conserved central acidic region and the C-terminal putative zinc fingers of mdm-2 may encode other functions.

scholarly journals ei24, a p53 Response Gene Involved in Growth Suppression and Apoptosis

2000 ◽  
Vol 20 (1) ◽  
pp. 233-241 ◽  
Author(s):  
Zhengming Gu ◽  
Cathy Flemington ◽  
Thomas Chittenden ◽  
Gerard P. Zambetti
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Apoptotic Cell ◽  
Functional Characterization ◽  
Growth Control ◽  
P53 Tumor Suppressor ◽  
Cycle Arrest ◽  
P53 Response

ABSTRACT DNA damage and/or hyperproliferative signals activate the wild-type p53 tumor suppressor protein, which induces a G1 cell cycle arrest or apoptosis. Although the mechanism of p53-mediated cell cycle arrest is fairly well defined, the p53-dependent pathway regulating apoptosis is poorly understood. Here we report the functional characterization of murine ei24 (also known asPIG8), a gene directly regulated by p53, whose overexpression negatively controls cell growth and induces apoptotic cell death. Ectopic ei24 expression markedly inhibits cell colony formation, induces the morphological features of apoptosis, and reduces the number of β-galactosidase-marked cells, which is efficiently blocked by coexpression of Bcl-XL. Theei24/PIG8 gene is localized on human chromosome 11q23, a region frequently altered in human cancers. These results suggest that ei24 may play an important role in negative cell growth control by functioning as an apoptotic effector of p53 tumor suppressor activities.

A Stapled p53 Helix Targets HDMX to Overcome Nutlin-3 Resistance and Reactivate the p53 Tumor Suppressor Pathway in Cancer

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2645-2645
Author(s):  
Federico Bernal ◽  
Mark Wade ◽  
Amy M. Silverstein ◽  
Gregory L. Verdine ◽  
Geoffrey M. Wahl ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Ubiquitin Ligase ◽  
Human Cancer ◽  
Transactivation Domain ◽  
Binding Interaction ◽  
P53 Tumor Suppressor ◽  
Cycle Arrest

Abstract p53 is a transcription factor that induces cell cycle arrest or apoptosis in response to DNA damage and cellular stress, and thereby plays a critical role in protecting cells from malignant transformation. The E3 ubiquitin ligase HDM2 controls p53 levels through a direct binding interaction that neutralizes the transactivation activity of p53 and targets it for degradation via the ubiquitylation-proteasomal pathway. Whereas the HDM2-homologue HDMX lacks ubiquitin ligase function, it participates in regulating the p53 axis by heterodimerizing with HDM2 and sequestering p53 through protein interaction. Loss of p53 activity, either by deletion, mutation, or HDM2/HDMX overexpression, is the most common defect in human cancer. Tumors expressing wild type p53 are rendered vulnerable by pharmacologic approaches that stabilize and upregulate p53. In this context, HDM2 and HDMX have emerged as independent therapeutic targets for restoring p53 activity and resensitizing cancer cells to apoptosis in vitro and in vivo. The small molecule nutlin-3 is an effective antagonist of the p53-HDM2 interaction. However, several studies have demonstrated the inability of nutlin-3 to disrupt the p53-HDMX complex, rendering tumor cells that overexpress HDMX nutlin-3-resistant. We have previously described the synthesis and characterization of a hydrocarbon-stapled alpha-helical p53 peptide (SAH-p53-8) that binds HDM2 with low nanomolar affinity, targets HDM2 in situ, and reactivates the p53 tumor suppressor pathway in HDM2-overexpressing osteosarcoma cells. We now report that SAH-p53-8 binds HDMX with even higher affinity, co-immunoprecipitates with endogenous HDMX, and induces apoptosis and cell cycle arrest in nutlin-3-resistant cancer cells that overexpress HDMX. Thus, by inserting a chemical staple into a peptide fragment of the p53 transactivation domain, we have generated the first bifunctional inhibitor of HDM2 and HDMX, enabling the investigation and pharmacologic modulation of both targets in human cancer.

scholarly journals MyoD induced cell cycle arrest is associated with increased nuclear affinity of the Rb protein.

1993 ◽  
Vol 4 (7) ◽  
pp. 705-713 ◽  
Author(s):  
A M Thorburn ◽  
P A Walton ◽  
J R Feramisco
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Dna Synthesis ◽  
Cell Cycle Arrest ◽  
S Phase ◽  
Tumor Suppressor Protein ◽  
G1 Phase ◽  
Induced Expression ◽  
Rb Protein ◽  
Cycle Arrest

In studying the mechanism through which the myogenic determination protein MyoD prevents entry into the S phase of the cell cycle, we have found a relationship between MyoD and the retinoblastoma (Rb) tumor suppressor protein. By direct needle microinjection of purified recombinant MyoD protein into quiescent fibroblasts, which were then induced to proliferate by serum, we found that MyoD arrested progression of the cell cycle, in agreement with studies utilizing expression constructs for MyoD. By studying temporal changes in cells injected with MyoD protein, it was found that MyoD did not prevent serum induced expression of the protooncogene c-Fos, an event that occurs in the G0 to G1 transition of the cycle. Injection of the MyoD protein as late as 8 h after the addition of serum still caused an inhibition in DNA synthesis, suggesting that MyoD inhibits the G1 to S transition as opposed to the G0 to G1 transition. MyoD injection did not prevent the expression of cyclin A. However MyoD injection did result in a block in the increase in Rb extractibility normally seen in late G1 phase cells. As this phenomenon is associated with the hyperphosphorylation of Rb at this point in the cell cycle and is correlated with progression into S phase, this provides further evidence that MyoD blocks the cycle late in G1.

scholarly journals Cyclin A Is a Functional Target of Retinoblastoma Tumor Suppressor Protein-mediated Cell Cycle Arrest

1999 ◽  
Vol 274 (39) ◽  
pp. 27632-27641 ◽  
Author(s):  
Karen E. Knudsen ◽  
Anne F. Fribourg ◽  
Matthew W. Strobeck ◽  
Jean-Marie Blanchard ◽  
Erik S. Knudsen
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Cyclin A ◽  
Tumor Suppressor Protein ◽  
Retinoblastoma Tumor Suppressor Protein ◽  
Retinoblastoma Tumor Suppressor ◽  
Cycle Arrest ◽  
Retinoblastoma Tumor

scholarly journals MDM4 Isoform Expression in Melanoma Supports an Oncogenic Role for MDM4-A

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Abdullah Alatawi ◽  
SoonJye Kho ◽  
Michael P. Markey
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
P53 Gene ◽  
Genomic Databases ◽  
P53 Tumor Suppressor ◽  
Cycle Arrest ◽  
Biopsy Specimens ◽  
Direct Mutation

The p53 tumor suppressor integrates upstream signals such as DNA damage and active oncogenes to initiate cell cycle arrest or apoptosis. This response is critical to halting inappropriate growth signals. As such, p53 activity is lost in cancer. In melanoma, however, the p53 gene is intact in a reported 94% of human cases. Rather than direct mutation, p53 is held inactive through interaction with inhibitory proteins. Here, we examine the expression of the two primary inhibitors of p53, MDM2 and MDM4, in genomic databases and biopsy specimens. We find that MDM4 is frequently overexpressed. Moreover, changes in splicing of MDM4 occur frequently and early in melanomagenesis. These changes in splicing must be considered in the design of therapeutic inhibitors of the MDM2/4 proteins for melanoma.

scholarly journals Recent Advances in p53

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 211
Author(s):  
Gabriella D’Orazi
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Transcription Factor ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Tumor Suppressor Protein ◽  
Cellular Functions ◽  
Tumor Suppressor Protein P53 ◽  
Cycle Arrest ◽  
Stress Signals

Tumor suppressor protein p53 (TP53) is a key transcription factor that, in response to various stress signals, regulates numerous genes involved in a broad range of cellular functions including DNA repair, apoptosis, cell cycle arrest, senescence, metabolism, etc [...]

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