Related Experiment Video
Updated: Jul 20, 2026
14:57
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2
S C Evans1, M Viswanathan, J D Grier
1Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, TX 77030, USA.
Oncogene
|August 9, 2001
Summary
Researchers discovered a new way the HDM2 protein regulates the p53 tumor suppressor. Alternate-splice forms of HDM2 found in lung tumors enhance p53 activity by trapping HDM2 in the cytoplasm.
Area of Science:
- Molecular Biology
- Oncology
- Cancer Genetics
Background:
- The HDM2 (human double minute 2) protein inhibits the p53 tumor suppressor.
- HDM2 is overproduced due to gene amplification in about 30% of sarcomas, inactivating p53.
- Altered HDM2 localization and function are implicated in cancer development.
Purpose of the Study:
- To investigate the role of alternate-splice forms of HDM2 in human tumors.
- To understand the mechanism by which these splice variants affect HDM2 and p53 function.
- To identify novel regulatory mechanisms of p53 tumor suppressor activity.
Main Methods:
- Immunohistochemistry was used to screen human tumors for HDM2 overproduction.
- Sequence analysis was performed on hdm2 mRNA variants.
- Transient transfection assays were employed to study protein interactions and cellular localization.
Main Results:
- High levels of HDM2 were detected in the cytoplasm of 25% of lung tumors, differing from its normal nuclear localization.
- Alternate-splice forms of hdm2 mRNA, lacking a nuclear localization signal and parts of the p53 binding domain, were identified.
- A specific splice variant, HDM2(ALT1), sequestered full-length HDM2 in the cytoplasm, disrupting HDM2-p53 interaction and enhancing p53 activity.
Conclusions:
- Alternate splicing of hdm2 represents a novel regulatory mechanism controlling HDM2 and p53 activity.
- Cytoplasmic sequestration of HDM2 by splice variants can restore p53 tumor suppressor function.
- These findings suggest potential therapeutic strategies targeting HDM2 splicing in cancer treatment.
Related Concept Videos
01:23Negative Regulator Molecules
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
02:36DNA Damage can Stall the Cell Cycle
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
02:34Inhibition of Cdk Activity
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
02:23Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
01:19Interactions Between Signaling Pathways
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:36DNA Damage Can Stall the Cell Cycle
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...