Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor

Related Experiment Videos

D H Teng1, W L Perry, J K Hogan

  • 1Myriad Genetics, Inc., Salt Lake City, Utah 84108, USA. tengd@myriad.com

Cancer Research
|October 23, 1997
PubMed

Insights

Mutations in the MKK4 gene, crucial for cell signaling, were found in approximately 3% of human cancer cell lines. These MKK4 alterations may indicate its role in suppressing tumor growth and metastasis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Mitogen-activated protein kinases (MAPK) are key regulators of cellular processes.
  • The MKK4 (MAPK kinase 4) pathway is involved in stress- and cytokine-induced apoptosis.
  • MKK4 links upstream MEKK1 to downstream stress-activated protein kinase (SAPK)/JNK1 and p38 MAPK.

Purpose of the Study:

  • To investigate the role of MKK4 in human cancers.
  • To identify mutations and deletions in the MKK4 gene in various cancer cell lines.

Main Methods:

  • Analysis of human tumor cell lines for homozygous deletions in the MKK4 locus.
  • Screening of cancer cell lines for MKK4 sequence variants (nonsense and missense mutations).
  • In vitro biochemical assays to assess the functionality of altered MKK4 proteins.

Main Results:

  • Homozygous deletions of MKK4 were identified in pancreatic and lung carcinoma cell lines.
  • Five MKK4 sequence variants (2 nonsense, 3 missense) were found in 88 human cancer cell lines.
  • Approximately 3% of analyzed cell lines (6 of 213) showed MKK4 coding mutations.
  • Four of five altered MKK4 proteins were non-functional in phosphorylating stress-activated protein kinase when stimulated by MEKK1.

Conclusions:

  • MKK4 alterations are present in a subset of human cancers.
  • Functional MKK4 mutations suggest a potential role as a tumor suppressor.
  • MKK4 may inhibit tumorigenesis and metastasis in specific cell types.

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...
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...
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

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.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
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...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

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...
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

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...