Related Experiment Video

Updated: Aug 9, 2026

Rapid Quantification of Mitogen-induced Blastogenesis in T Lymphocytes for Identifying Immunomodulatory Drugs
08:13

Rapid Quantification of Mitogen-induced Blastogenesis in T Lymphocytes for Identifying Immunomodulatory Drugs

Published on: December 27, 2016

Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed,

Brian K Law1, Anna Chytil, Nancy Dumont

  • 1Department of Cancer Biology. Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. brian.k.law@vanderbilt.edu

Molecular and Cellular Biology
|November 6, 2002
PubMed

Insights

Transforming growth factor beta (TGF-beta) normally stops cell growth but not in many cancers. Rapamycin enhances TGF-beta

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Transforming growth factor beta (TGF-beta) is a cell growth inhibitor for most epithelial cells.
  • Many human carcinomas resist TGF-beta's growth-inhibitory effects, indicating a loss of this tumor suppressor function.
  • TGF-beta signaling is crucial in tumor suppression, with its loss accelerating tumorigenesis in mouse models.

Purpose of the Study:

  • To identify agents that can potentiate TGF-beta's growth arrest effects.
  • To investigate the synergistic effects of rapamycin and TGF-beta on cell proliferation, particularly in cancer cells resistant to TGF-beta.
  • To elucidate the molecular mechanisms underlying the combined inhibition of cell proliferation by TGF-beta and rapamycin.

Main Methods:

  • Screening for agents that enhance TGF-beta-induced growth arrest.
  • Treating various cell lines, including transformed and carcinoma cells, with TGF-beta and rapamycin.
  • Analyzing TGF-beta receptor levels and FKBP12 dissociation.
  • Assessing Cdk2 kinase activity, its associated proteins (p21, p27, p130, p107, E2F4), and Cdk2 phosphorylation status.

Main Results:

  • Rapamycin cooperated with TGF-beta to induce growth arrest in multiple cell lines, including those resistant to TGF-beta alone.
  • This synergy was observed even in cells transformed with E2F1, c-Myc, and (V12)H-Ras.
  • The combined treatment suppressed Cdk2 kinase activity by increasing p21 and p27 binding and decreasing Cdk2 phosphorylation, alongside reduced binding of p130, p107, and E2F4.

Conclusions:

  • Rapamycin enhances TGF-beta's ability to inhibit cell proliferation in both normal and cancerous cells.
  • The cooperation between TGF-beta and rapamycin leads to cell cycle arrest via the inhibition of Cdk2 kinase activity.
  • This study identifies a potential therapeutic strategy combining TGF-beta and rapamycin to overcome resistance in human carcinomas.

More Related Videos

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

Development and Application of Rapamycin-regulated Tyrosine Phosphatases06:56

Development and Application of Rapamycin-regulated Tyrosine Phosphatases

Published on: September 6, 2024

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.
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...
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...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
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...