Transforming growth factor beta 1 promotes cell cycle exit through the cyclin-dependent kinase inhibitor p21 in the

Julie A Siegenthaler1, Michael W Miller

  • 1Department of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA.

Insights

Transforming growth factor beta1 (TGFbeta1) promotes cell cycle exit during brain development. This process is linked to increased expression of the p21 protein in neural progenitor cells.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Cell Biology

Background:

  • Cortical neurogenesis requires precise regulation of cell proliferation and cell cycle exit.
  • Transforming growth factor beta1 (TGFbeta1) is present in developing cerebral cortex regions and is implicated in cell cycle control.

Purpose of the Study:

  • To investigate if TGFbeta1 promotes cell cycle exit in the cortical ventricular zone (VZ).
  • To determine if TGFbeta1 modulates cell cycle proteins, specifically cyclin D1, p27, and p21.

Main Methods:

  • Treatment of cortical VZ cells with TGFbeta1.
  • Analysis of cell cycle length, fraction of cycling cells, and cell cycle exit.
  • Assessment of cell cycle protein expression (cyclin D1, p27, p21) via quantitative analysis.

Main Results:

  • TGFbeta1 treatment reduced the fraction of VZ-cycling cells by 21% and increased cell cycle exit by 24%.
  • TGFbeta1 selectively upregulated p21 expression in the VZ.
  • High p21 expression correlated with VZ cells exiting the cell cycle, and TGFbeta1 increased the number of p21-positive cells exiting the cell cycle.

Conclusions:

  • TGFbeta1 actively promotes cell cycle exit during cortical development.
  • Upregulation of p21 is a key event associated with TGFbeta1-induced cell cycle exit.
  • The mechanism of TGFbeta1-induced cell cycle exit involves the p21 protein.

Related Concept Videos

Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
Positive Regulator Molecules02:39

Positive Regulator Molecules

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.
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...
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...
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
Molecular Factors Affecting Cell Division01:27

Molecular Factors Affecting Cell Division

Several external and internal factors influence the initiation and inhibition of cell division. For instance, the death of nearby cells or the release of human growth hormone (hGH) promotes cell division. In contrast, lack of hGH or crowding of cells can inhibit cell division.
Several proteins function as internal regulators to ensure each cell cycle stage is completed faithfully before proceeding to the next. Regulator molecules may act directly or influence the activity or production of other...