Related Experiment Video

Updated: Jun 11, 2026

Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
09:37

Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells

Published on: August 25, 2021

HDM2 impairs Noxa transcription and affects apoptotic cell death in a p53/p73-dependent manner in neuroblastoma

Yun Shi1, Hisanori Takenobu, Kenji Kurata

  • 1Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.

European Journal of Cancer (Oxford, England : 1990)
|July 2, 2010
PubMed

Insights

Increased HDM2 expression worsens prognosis in neuroblastoma (NB) by suppressing Noxa, a key apoptosis regulator. Reducing HDM2 restores chemotherapy sensitivity in NB cells, highlighting a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • HDM2 negatively regulates p53 tumor suppressor activity.
  • Increased HDM2 expression, often due to SNP309 polymorphism, is linked to various cancers, including neuroblastoma (NB).
  • MYCN-amplified NB is an aggressive subtype with poor prognosis.

Purpose of the Study:

  • To investigate the role of HDM2 in MYCN-amplified NB prognosis and its impact on chemotherapy response.
  • To elucidate the mechanism by which HDM2 influences NB cell sensitivity to doxorubicin (Doxo).

Main Methods:

  • Small interfering RNA (siRNA) to knockdown HDM2 expression.
  • Quantitative real-time PCR and Western blotting to assess mRNA and protein levels of Noxa.
  • Cell viability assays to determine sensitivity to doxorubicin.
  • Chromatin immunoprecipitation (ChIP) assays to evaluate p53/p73 binding to the Noxa promoter.

Main Results:

  • Elevated HDM2 expression correlates with a worse prognosis in MYCN-amplified NB patients.
  • HDM2 knockdown upregulates Noxa (mRNA/protein) and resensitizes Doxo-resistant NB cells, an effect dependent on p53 status.
  • HDM2 overexpression confers Doxo resistance in sensitive NB cells.
  • HDM2 inhibits p53/p73 binding to the Noxa promoter, suppressing its transcription and downstream apoptosis.

Conclusions:

  • HDM2 plays a critical role in mediating doxorubicin resistance in neuroblastoma.
  • The HDM2-Noxa axis, regulated by p53/p73, represents a potential therapeutic vulnerability in NB.
  • Targeting HDM2 may restore chemosensitivity in drug-resistant neuroblastoma.

More Related Videos

Identifying, Diagnosing, and Grading Malignant Peripheral Nerve Sheath Tumors in Genetically Engineered Mouse Models08:57

Identifying, Diagnosing, and Grading Malignant Peripheral Nerve Sheath Tumors in Genetically Engineered Mouse Models

Published on: May 17, 2024

Related Concept Videos

Abnormal Proliferation02:23

Abnormal 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...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Interactions Between Signaling Pathways01:19

Interactions 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...
DNA Damage can Stall the Cell Cycle02:36

DNA 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...
DNA Damage Can Stall the Cell Cycle02:36

DNA 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...