Related Experiment Video
Updated: Aug 5, 2025
09:45
Mosaic Zebrafish Transgenesis for Functional Genomic Analysis of Candidate Cooperative Genes in Tumor Pathogenesis
Published on: March 31, 2015
11.3K
MYCN Amplification, along with Wild-Type RB1 Expression, Enhances CDK4/6 Inhibitors' Efficacy in Neuroblastoma Cells
Piergiuseppe De Rosa1, Federica Severi1, Suleman Khan Zadran1
1Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy.
International Journal of Molecular Sciences
|March 29, 2023
Summary
High MYCN expression in neuroblastoma (NB) drives poor prognosis by inactivating RB, revealing RB
Area of Science:
- Pediatric Oncology
- Molecular Biology
- Cell Cycle Regulation
Background:
- Neuroblastoma (NB) is a leading cause of pediatric cancer mortality.
- MYCN amplification is a key driver of poor prognosis in NB.
- Understanding cell cycle regulation in NB is crucial for targeted therapies.
Purpose of the Study:
- Investigate the role of MYCN in the G1/S cell cycle transition in NB.
- Identify novel therapeutic targets for MYCN-amplified NB.
- Elucidate the interaction between MYCN and RB1 in NB cell cycle control.
Main Methods:
- Luciferase reporter assays to assess promoter activity.
- Cell cycle synchronization and Western blotting to analyze RB phosphorylation.
- CRISPR interference (CRISPRi) for conditional RB1 knockdown in NB cell lines.
Main Results:
- High E2F3 and MYCN expression correlate with poor NB prognosis.
- MYCN bypasses RB1 function by increasing E2F3 promoter activity.
- MYCN overexpression induces RB1 hyperphosphorylation, leading to RB1 inactivation.
- RB1 knockdown does not affect proliferation in MYCN-amplified NB, but a non-phosphorylatable RB mutant impairs it.
Conclusions:
- RB1 plays a dispensable role in regulating the cell cycle of MYCN-amplified NB.
- The interaction between MYCN and RB1 suggests targeting cyclin/CDK complexes for NB treatment.
- This study provides a rationale for using CDK inhibitors in NB with MYCN amplification and high RB1 expression.
Related Concept Videos
02:34Inhibition of Cdk Activity
4.8K
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...
4.8K
02:23Abnormal Proliferation
4.6K
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...
4.6K
01:20The Retinoblastoma Gene
4.2K
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.2K
03:03mTOR Signaling and Cancer Progression
3.8K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.8K
02:38Mitogens and the Cell Cycle
6.6K
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.6K