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000299495 041__ $$aEnglish
000299495 082__ $$a570
000299495 1001_ $$aŠkapik, Ivana Paskov$$b0
000299495 245__ $$aMaintenance of p-eIF2α levels by the eIF2B complex is vital for colorectal cancer.
000299495 260__ $$a[London]$$bNature Publishing Group UK$$c2025
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000299495 500__ $$aZMBH Alliance / EMBO J, (2025), 44: 2075 - 2105
000299495 520__ $$aProtein synthesis is an essential process, deregulated in multiple tumor types showing differential dependence on translation factors compared to untransformed tissue. We show that colorectal cancer (CRC) with loss-of-function mutation in the APC tumor suppressor depends on an oncogenic translation program regulated by the ability to sense phosphorylated eIF2α (p-eIF2α). Despite increased protein synthesis rates following APC loss, eIF2α phosphorylation, typically associated with translation inhibition, is enhanced in CRC. Elevated p-eIF2α, and its proper sensing by the decameric eIF2B complex, are essential to balance translation. Knockdown or mutation of eIF2Bα and eIF2Bδ, two eIF2B subunits responsible for sensing p-eIF2α, impairs CRC viability, demonstrating that the eIF2B/p-eIF2α nexus is vital for CRC. Specifically, the decameric eIF2B linked by two eIF2Bα subunits is critical for translating growth-promoting mRNAs which are induced upon APC loss. Depletion of eIF2Bα in APC-deficient murine and patient-derived organoids establishes a therapeutic window, validating eIF2Bα as a target for clinical intervention. In conclusion, we demonstrate how the expression of the oncogenic signature in CRC is crucially controlled at the translational level.
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000299495 650_7 $$2Other$$aAPC
000299495 650_7 $$2Other$$aColorectal Cancer
000299495 650_7 $$2Other$$aTranslation
000299495 650_7 $$2Other$$aeIF2B
000299495 650_7 $$2Other$$aeIF2α
000299495 7001_ $$aGiacomelli, Chiara$$b1
000299495 7001_ $$aHahn, Sarah$$b2
000299495 7001_ $$aDeinlein, Hanna$$b3
000299495 7001_ $$00000-0002-8270-5738$$aGallant, Peter$$b4
000299495 7001_ $$00000-0002-7595-3901$$aDiebold, Mathias$$b5
000299495 7001_ $$00000-0002-0842-7530$$aBiayna, Josep$$b6
000299495 7001_ $$aHendricks, Anne$$b7
000299495 7001_ $$aOlimski, Leon$$b8
000299495 7001_ $$aOtto, Christoph$$b9
000299495 7001_ $$aKastner, Carolin$$b10
000299495 7001_ $$aWolf, Elmar$$b11
000299495 7001_ $$aSchülein-Völk, Christina$$b12
000299495 7001_ $$aMaurus, Katja$$b13
000299495 7001_ $$aRosenwald, Andreas$$b14
000299495 7001_ $$0P:(DE-HGF)0$$aSchleussner, Nikolai$$b15
000299495 7001_ $$0P:(DE-He78)5da14633266cbfff7746cf529c110673$$aJackstadt, Rene-Filip$$b16$$udkfz
000299495 7001_ $$aSchlegel, Nicolas$$b17
000299495 7001_ $$aGermer, Christoph-Thomas$$b18
000299495 7001_ $$aBushell, Martin$$b19
000299495 7001_ $$00000-0002-0376-6533$$aEilers, Martin$$b20
000299495 7001_ $$00000-0003-2053-0909$$aSchmidt, Stefanie$$b21
000299495 7001_ $$00000-0001-7777-0909$$aWiegering, Armin$$b22
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