Related Experiment Video

Updated: May 12, 2026

Assaying Protein Kinase Activity with Radiolabeled ATP
08:05

Assaying Protein Kinase Activity with Radiolabeled ATP

Published on: May 26, 2017

Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation

Xavier Deschênes-Simard1, Marie-France Gaumont-Leclerc, Véronique Bourdeau

  • 1Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada.

Genes & Development
|April 20, 2013
PubMed

Insights

Aberrant growth signaling and short telomeres trigger cellular senescence via proteasome-dependent protein degradation. Inhibiting this process, known as senescence-associated protein degradation (SAPD), allows cell transformation, revealing a key mechanism in cancer development.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Constitutive activation of growth factor signaling pathways paradoxically induces cellular senescence, a cell cycle arrest that prevents cancer.
  • Oncogenic Ras signaling typically triggers senescence in primary cells, inhibiting transformation.

Purpose of the Study:

  • To investigate the mechanism by which ERK/MAP kinase signaling regulates oncogene-induced senescence.
  • To identify the downstream targets and pathways involved in ERK-mediated senescence.
  • To explore the role of senescence-associated protein degradation (SAPD) in cancer development.

Main Methods:

  • Genetic inactivation of Erk2 and RNA interference (RNAi)-mediated knockdown of ERK1/ERK2.
  • MEK inhibitors to attenuate ERK/MAP kinase signaling.
  • Proteasome inhibition assays and analysis of protein degradation.
  • RNAi-mediated inactivation of senescence-associated protein degradation (SAPD) targets.
  • Analysis of viral oncoproteins (E1A, E6, E7) and their effect on SAPD.
  • Immunohistochemical analysis of human prostate neoplasms.

Main Results:

  • Attenuation of ERK/MAP kinase signaling prevented oncogenic Ras-induced senescence, enabling cell transformation.
  • ERK-mediated senescence involves proteasome-dependent degradation of key cellular proteins (SAPD), affecting cell cycle, mitochondria, migration, RNA metabolism, and signaling.
  • SAPD was observed in Ras-transformed cells and cells with short telomeres.
  • Inactivation of SAPD targets could restore senescence in transformed cells or induce senescence in normal cells.
  • Anti-senescence viral oncoproteins E1A, E6, and E7 inhibited SAPD.
  • Human prostate benign lesions showed high phosphorylated ERK and senescence markers, correlating with low STAT3 (a SAPD target).

Conclusions:

  • A novel mechanism links aberrant growth signaling and short telomeres to protein degradation and cellular senescence.
  • ERK/MAP kinase signaling is crucial for initiating senescence through SAPD.
  • SAPD is a critical tumor suppressor mechanism, and its inhibition contributes to cancer development.
  • STAT3 is identified as a key target protein degraded during senescence.

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...
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...
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...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
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...
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...