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Related Concept Videos

The Ras Gene02:38

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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.
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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...
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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.
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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...
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Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
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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...
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Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities.

Jacob A Herman1, Romario R Romain1, Pia Hoellerbauer2

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|October 3, 2022
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Summary

Cancer cells with RAS or MAPK signaling are vulnerable to BubR1 inhibition. This vulnerability arises because these pathways disrupt chromosome segregation, increasing reliance on BubR1 for maintaining the spindle assembly checkpoint and error correction.

Keywords:
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Area of Science:

  • Cell Biology
  • Cancer Biology
  • Genetics

Background:

  • Aneuploidy, an abnormal chromosome number, is prevalent in tumors and drives their development.
  • Kinetochores are crucial protein complexes that ensure accurate chromosome segregation during cell division.
  • BubR1 is vital for kinetochore function, acting in both error correction and the spindle assembly checkpoint (SAC), and is a cancer therapeutic target.

Purpose of the Study:

  • To investigate the oncogenic pressures driving cancer-specific dependency on BubR1.
  • To determine if BubR1's role in the SAC or error correction underlies this dependency.
  • To identify the molecular mechanisms linking oncogenic signaling to BubR1 vulnerability.

Main Methods:

  • Utilized a genetically controlled transformation model.
  • Analyzed glioblastoma tumor isolates.
  • Investigated the impact of RAS and MAPK signaling on kinetochore function and chromosome segregation.

Main Results:

  • Constitutive RAS or MAPK signaling is essential for the cancer-specific vulnerability to BubR1 inhibition.
  • The MAPK pathway hyperstimulates kinetochore kinases, impairing chromosome segregation.
  • This impairment increases cellular dependence on BubR1 for error correction and SAC maintenance.

Conclusions:

  • RAS/MAPK signaling creates a dependency on BubR1 by compromising chromosome segregation.
  • BubR1's dual roles in error correction and SAC are critical for cancer cells under oncogenic stress.
  • This study reveals an oncogenic trigger for a cancer-specific defect in chromosome segregation.