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The Ras Gene02:38

The Ras Gene

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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.
Ras is a...
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Cell Signaling Feedback Loops01:07

Cell Signaling Feedback Loops

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Positive and negative feedback loops are crucial for regulating biological signaling systems. These feedback loops are processes that connect output signals to their inputs.
Negative feedback loops
Most signaling systems have negative feedback loops that can perform different functions such as output limiter, and adaptation.
Output limiter
Upon receiving an input signal, the cellular response rapidly increases until a threshold is reached. Beyond this threshold, a negative feedback loop...
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The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

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Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
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mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

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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.
The mTOR pathway or the...
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PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

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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...
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Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

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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...
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Updated: Sep 10, 2025

Combined Use of Tail Vein Metastasis Assays and Real-Time In Vivo Imaging to Quantify Breast Cancer Metastatic Colonization and Burden in the Lungs
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STAT1 と YAP1 の間のフィードフォワードループは,脂質生物合成を刺激し,腫瘍の成長を加速し,変異したKRAS大腸がんにおける化学療法耐性を促進する.

Shuo Wang1, Shiqi Diao2,3, Hyungdong Kim2,3

  • 1Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, QC, Canada. shuo.wang@ladydavis.ca.

Communications biology
|August 25, 2025
PubMed
まとめ

STAT1は,KRAS変異性がんにおける結腸直腸腫瘍の成長と生存を促進し,脂質の産生を促進する. STAT1-YAP1経路をターゲットにすることで,治療に抵抗するKRAS変異性大腸がんに対する新しい戦略が提供されます.

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Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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科学分野:

  • 腫瘍学
  • 分子生物学
  • 癌 研究

背景:

  • シグナルトランスデューサーとトランスクリプション1 (STAT1) のアクティベータは,伝統的に抗腫瘍の役割を持っています.
  • 腫瘍状態では,STAT1は不明なメカニズムによって生存促進機能を発揮する.
  • 変異したKRASは多くの結腸直腸がんの主要な原動力であり,しばしば予後不良に関連しています.

研究 の 目的:

  • ワイルド型または変異KRASを持つ大腸直腸腫瘍細胞におけるSTAT1の特定の役割を調査する.
  • 変異したKRASの文脈でSTAT1が腫瘍の生存と増殖を促進する分子メカニズムを解明する.
  • KRAS変異性大腸癌の潜在的治療標的を特定する.

主な方法:

  • ワイルド型または変異KRASを有する同位結腸腫瘍細胞系を使用した.
  • STAT1調節遺伝子を特定するために遺伝子発現プロファイリングを行いました.
  • S727におけるSTAT1リン酸化の役割とその脂質生物合成経路への影響を調査した.
  • STAT1- YAP1- TEAD4軸とその治療抵抗への貢献を分析した.

主要な成果:

  • STAT1は,KRAS変異の結腸直腸腫瘍細胞の生存と増殖を特異的に促進する.
  • STAT1は,STAT1 S727のリン酸化に依存した方法で,SREBP1およびSREBP2を含むステロールおよび脂質生物合成遺伝子を上調する.
  • STAT1,YAP1,TEAD4を含む陽性フィードバックループは,突然変異したKRAS細胞における脂質の産生と腫瘍の成長を増幅する.
  • STAT1- YAP1軸は,メバロナート経路阻害剤とEGFRを標的とした治療に耐性を与える.

結論:

  • STAT1は,脂質生物合成を促進することによって,突然変異したKRAS大腸がんの生存に重要な役割を果たします.
  • STAT1- YAP1経路は,この文脈で治療抵抗性の重要な媒介者である.
  • STAT1- YAP1の相互作用を標的とした治療は,突然変異したKRAS大腸がんに対する有望な治療戦略です.