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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...
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
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...
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
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...
M-Cdk Drives Transition Into Mitosis02:15

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Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...

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CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis.

Mirella Lazarov1, Yoshiaki Kubo, Ti Cai

  • 1VAPalo Alto Healthcare System, Palo Alto and the Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.

Nature Medicine
|October 3, 2002
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Summary

Oncogenic Ras initially suppresses cell growth by reducing cyclin-dependent kinase (CDK) 4. However, co-expression of CDK4 drives invasive neoplasia, highlighting CDK4

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Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Ras signaling is crucial in neoplasia but can paradoxically suppress normal cell proliferation.
  • Understanding Ras-mediated cell cycle regulation is key to cancer prevention.

Purpose of the Study:

  • To investigate the role of oncogenic Ras in regulating cyclin-dependent kinase (CDK) 4 expression.
  • To determine if CDK4 co-expression can overcome Ras-induced growth suppression and promote tumorigenesis.

Main Methods:

  • Analysis of oncogenic Ras effects on CDK4 expression in primary epidermal cells.
  • Assessment of cell cycle progression and G1 arrest.
  • Evaluation of CDK4 co-expression in inducing invasive human neoplasia and its dependence on kinase function and cyclin D1.

Main Results:

  • Oncogenic Ras transiently decreases CDK4 expression, causing G1 cell cycle arrest.
  • CDK4 co-expression overrides Ras-induced growth suppression, leading to invasive squamous cell carcinoma-like neoplasia.
  • Tumorigenesis is dependent on CDK4 kinase activity and requires cyclin D1.
  • Ras and CDK4 promote resistance to INK4 inhibitors by altering cyclin D/E complex composition.

Conclusions:

  • Oncogenic Ras plays a novel role in regulating CDK4 expression.
  • CDK4 suppression is critical for preventing uncontrolled cell growth.
  • Targeting CDK4 may offer therapeutic strategies against Ras-driven cancers.