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Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition 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...
Inhibition of CDK Activity02:34

Inhibition 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...
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Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
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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...
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Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...

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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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AKT Activation by Pdcd4 Knockdown Up-Regulates Cyclin D1 Expression and Promotes Cell Proliferation.

Xiaoling Guo1, Wenjuan Li, Qing Wang

  • 1Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY, USA.

Genes & Cancer
|March 7, 2012
PubMed
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Loss of tumor suppressor Pdcd4 promotes cancer by activating AKT and NF-κB signaling pathways. This leads to increased cyclin D1 expression and cell proliferation, driving tumor development.

Keywords:
AKTIKKNF-κBPdcd4cyclin D1

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Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Signaling

Background:

  • Programmed cell death 4 (Pdcd4) is a tumor suppressor that inhibits cancer progression.
  • Loss of Pdcd4 function is implicated in neoplastic transformation and tumor invasion.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which Pdcd4 loss promotes tumor development.
  • To investigate the role of AKT and NF-κB signaling in Pdcd4-mediated regulation of cell proliferation and cyclin D1 expression.

Main Methods:

  • Utilized knockdown and ectopic expression of Pdcd4, AKT, and NF-κB pathway components (IKKα/β).
  • Assessed cell proliferation, cyclin D1 expression, and promoter activity via reporter assays.
  • Analyzed protein phosphorylation and kinase activity of AKT and IKK.

Main Results:

  • Pdcd4 knockdown increased cell proliferation and cyclin D1 expression, mediated by NF-κB activation.
  • Pdcd4 loss activated the AKT pathway, leading to increased AKT phosphorylation and kinase activity.
  • AKT activation was essential for NF-κB activation, subsequent cyclin D1 upregulation, and enhanced cell proliferation.

Conclusions:

  • Pdcd4 loss activates the AKT signaling pathway, which in turn activates NF-κB.
  • This AKT/NF-κB axis drives elevated cyclin D1 expression and promotes cell proliferation, contributing to tumor development.
  • Pdcd4 acts as a crucial regulator of AKT activity, implicating its loss in oncogenesis.