Related Experiment Video

Updated: Jun 13, 2026

Genetic Profiling and Genome-Scale Dropout Screening to Identify Therapeutic Targets in Mouse Models of Malignant Peripheral Nerve Sheath Tumor
09:33

Genetic Profiling and Genome-Scale Dropout Screening to Identify Therapeutic Targets in Mouse Models of Malignant Peripheral Nerve Sheath Tumor

Published on: August 25, 2023

Transcriptional repression of SKP2 is impaired in MYCN-amplified neuroblastoma

Daniel Muth1, Seda Ghazaryan, Isabella Eckerle

  • 1Department of Tumor Genetics, German Cancer Research Center, University of Heidelberg, Heidelberg, Germany.

Cancer Research
|April 29, 2010
PubMed

Insights

MYCN-amplified neuroblastoma cells show increased SKP2 expression due to MYCN deregulation. Restoring pRB activity with CDK4 inhibitors can reestablish SKP2 transcriptional control, impacting cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • SKP2 (S-phase kinase-associated protein 2) is a cell cycle regulator overexpressed in cancers.
  • SKP2 promotes p27 degradation, contributing to tumor cell dedifferentiation.
  • Mechanisms of impaired SKP2 transcriptional control in tumors are poorly understood.

Purpose of the Study:

  • Investigate SKP2 regulation in neuroblastoma, a model for increasing aggressiveness.
  • Determine the role of MYCN amplification in SKP2 overexpression.
  • Identify therapeutic strategies to restore SKP2 transcriptional control.

Main Methods:

  • Neuroblastoma cell lines with varying MYCN amplification levels.
  • Reporter assays to measure SKP2 core promoter activity.
  • Chromatin immunoprecipitation to assess protein-DNA interactions.
  • Pharmacological inhibition of CDK4, CDK2, p53, and p21 pathways.

Main Results:

  • MYCN-amplified neuroblastoma exhibits significantly higher SKP2 promoter activity.
  • SKP2 activation is mediated by an E2F-binding site at the transcriptional start site.
  • MYCN amplification leads to reduced pRB-E2F1 complex binding to the SKP2 promoter.
  • CDK4 inhibition restores pRB activity and normalizes SKP2 transcription.

Conclusions:

  • MYCN amplification drives SKP2 overexpression in neuroblastoma via CDK4-induced abrogation of pRB-E2F1 complexes.
  • Targeting CDK4 offers a potential therapeutic strategy for MYCN-amplified neuroblastomas.
  • SKP2 regulation is critically dependent on MYCN and pRB status in neuroblastoma.

More Related Videos

Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells09:37

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

Published on: August 25, 2021

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...
Induced Pluripotent Stem Cells01:06

Induced Pluripotent Stem Cells

Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic cells are...
Somatic to iPS Cell Reprogramming01:29

Somatic to iPS Cell Reprogramming

Reprogramming alters the gene expression in somatic cells, transforming them into induced pluripotent stem (iPS) cells over several generations. Scientists can reprogram cells by introducing genes for four transcription factors—Oct4, Sox2, Klf4, and c-Myc (OSKM) by viral or non-viral methods. These factors are also known as Yamanaka factors after Shinya Yamanaka, who first generated iPS cells using mouse skin cells. Yamanaka was awarded the Nobel Prize in Physiology or Medicine in 2012 for this...
Master Transcription Regulators02:23

Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

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...