The regulation of bcr-abl in hypoxia is through the mTOR pathway

Clapper, Erin; Trapani, Giovanna Di; Tonissen, Kathryn Fay

doi:10.1080/10428194.2020.1849679

Cited by 6 publications

(4 citation statements)

References 40 publications

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“…Normally, the tyrosine kinase protein encoded by ABL1 is negatively regulated by its N-terminal myristoyl peptide ( Radi et al, 2013 ), the sequence encoding which is deleted due to the fusion of BCR and ABL1 genes, resulting in the breaking of this self-inhibition balance and the continuous activation of tyrosine kinase. ATP-competitive inhibitors targeting ABL1 have greatly improved the prognosis of CML patients, but drug resistance ( Devos et al, 2021 ), disease progression ( Kakiuchi et al, 2021 ), or some serious adverse events occurring during treatment bring challenges to clinical practices ( Castagnetti et al, 2021 ; Clapper et al, 2021 ), especially drug resistance caused by BCR::ABL1 mutations ( Mian et al, 2021 ). In the construction of cell lines carrying BCR::ABL1 mutants, we selected 1–2 common mutant sites in four regions including the ATP-binding loop (248–256 amino acids), TKI-binding site, catalytic domain (350–363 amino acids), and activation loop, which are the E255, T315, F359, L387, F486, and including T315 compound mutations.…”

Section: Discussionmentioning

confidence: 99%

The proteolysis targeting chimera GMB-475 combined with dasatinib for the treatment of chronic myeloid leukemia with BCR::ABL1 mutants

Wu²,

Wang³

et al. 2022

Front. Pharmacol.

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Patients with chronic myeloid leukemia (CML) show resistance to tyrosine kinase inhibitors (TKIs) targeting ABL1 due to the emergence of BCR::ABL1 mutants, especially compound mutants during the treatment, which brings great challenges to clinical practice. Combination therapy is an effective strategy for drug resistance. GMB-475, a proteolysis targeting chimera (PROTAC) targeting the myristoyl pocket of ABL1 in an allosteric manner, degrades the BCR::ABL1 through the ubiquitin–proteasome pathway. In this study, we combined GMB-475 with orthosteric TKIs targeting ABL1 to overcome resistance. We constructed Ba/F3 cells carrying BCR::ABL1 mutants by gene cloning technology and compared the effects of combination therapy with those of monotherapy on the biological characteristics and signaling pathways in CML cells. We found that the effects of ABL1 inhibitors, including imatinib, dasatinib, ponatinib, and ABL001, on growth inhibition and promoting apoptosis of Ba/F3 cells with BCR::ABL1 mutants, especially compound mutants, were weakened. GMB-475 combined with TKIs, especially dasatinib, synergistically inhibited growth, promoted apoptosis, and blocked the cell cycle of Ba/F3 cells carrying BCR::ABL1 mutants and synergistically blocked multiple molecules in the JAK-STAT pathway. In conclusion, dasatinib enhanced the antitumor effect of GMB-475; that is, the combination of PROTAC targeting ABL1 in an allosteric manner and orthosteric TKIs, especially dasatinib, provides a novel idea for the treatment of CML patients with BCR::ABL1 mutants in clinical practice.

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Section: Discussionmentioning

confidence: 99%

The proteolysis targeting chimera GMB-475 combined with dasatinib for the treatment of chronic myeloid leukemia with BCR::ABL1 mutants

Wu²,

Wang³

et al. 2022

Front. Pharmacol.

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“…Does phosphorylation of GhRPS6 affect its function? Ribosomal biogenesis involves the manufacture and processing of ribosomal RNAs, the biosynthesis of ribosomal proteins, and the transport of ribosomal proteins to the nucleolus to assemble the preribosomal particles [40][41][42][43][44][45][46][47][48]. Existing literature shows that ribosomal proteins are involved in various physiological functions of cells and have been reported to regulate plant growth [41].…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Analysis of Ribosomal Protein GhRPS6 and Its Role in Cotton Verticillium Wilt Resistance

Zhu

Zhang

Zhou

et al. 2021

IJMS

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Verticillium wilt is threatening the world’s cotton production. The pathogenic fungus Verticillium dahliae can survive in the soil in the form of microsclerotia for a long time, colonize through the root of cotton, and invade into vascular bundles, causing yellowing and wilting of cotton leaves, and in serious cases, leading to plant death. Breeding resistant varieties is the most economical and effective method to control Verticillium wilt. In previous studies, proteomic analysis was carried out on different cotton varieties inoculated with V. dahliae strain Vd080. It was found that GhRPS6 was phosphorylated after inoculation, and the phosphorylation level in resistant cultivars was 1.5 times than that in susceptible cultivars. In this study, knockdown of GhRPS6 expression results in the reduction of SA and JA content, and suppresses a series of defensive response, enhancing cotton plants susceptibility to V. dahliae. Overexpression in Arabidopsis thaliana transgenic plants was found to be more resistant to V. dahliae. Further, serines at 237 and 240 were mutated to phenylalanine, respectively and jointly. The transgenic Arabidopsis plants demonstrated that seri-237 compromised the plant resistance to V. dahliae. Subcellular localization in Nicotiana benthamiana showed that GhRPS6 was localized in the nucleus. Additionally, the pathogen inoculation and phosphorylation site mutation did not change its localization. These results indicate that GhRPS6 is a potential molecular target for improving resistance to Verticillium wilt in cotton. This lays a foundation for breeding disease-resistant varieties.

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“…In mammalian cells, hypoxia-induced HIF-1α activity reduces growth by suppressing the activity of the mammalian Target of Rapamycin (mTOR) 70,71,72,73,74 , a major regulator of anabolic metabolism 75 . It is of interest therefore that TOR signalling activity, as assayed by phosphorylated ribosomal protein S6 (pS6) immunoreactivity, progressively decreases during the growth of L3 wing imaginal discs 76,77 , an observation that we confirmed by Western blot analysis (Extended Data Fig.…”

Section: Sima/hif-1α Dampens Tor Signalling Through Activation Of Scy...mentioning

confidence: 99%

Growth-induced physiological hypoxia correlates with growth deceleration during normal development

Zhao,

Alexandre,

Kelly

et al. 2024

Preprint

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Growth deceleration is a universal feature of growth during development: most organs and tissues slow down their growth rate much before growth termination. Using transcriptomics analysis, we show that during their two-day period of growth deceleration, wing imaginal discs ofDrosophilaundergo a progressive metabolic shift away from oxidative phosphorylation and towards glycolysis. We then develop an ultra-sensitive reporter HIF-1α activity, which reveals that imaginal discs become increasingly hypoxic during development in normoxic conditions, suggesting that limiting oxygen supply could underlie growth deceleration. Growth is energetically expensive and thus expected to contribute, indirectly, to oxygen consumption. Indeed, excess TOR signalling, a key stimulator of growth, triggers hypoxia locally and systemically, highlighting the need to rein in growth when oxygen becomes limiting. This is achieved by a negative feedback loop whereby the classic TOR-inhibitory function of HIF-1α is deployed in response to developmental hypoxia. The absence of Sima/HIF-1α leads to cellular stress, which is alleviated by reduced TOR signalling. Conversely, a small increase in oxygen supply reduces the stress induced by excess TOR activity. We conclude that mild hypoxia is a normal feature of organ development and that Sima/HIF-1α prevents growth-induced oxygen demand from exceeding supply.

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The regulation of bcr-abl in hypoxia is through the mTOR pathway

Cited by 6 publications

References 40 publications

The proteolysis targeting chimera GMB-475 combined with dasatinib for the treatment of chronic myeloid leukemia with BCR::ABL1 mutants

The proteolysis targeting chimera GMB-475 combined with dasatinib for the treatment of chronic myeloid leukemia with BCR::ABL1 mutants

Genome-Wide Analysis of Ribosomal Protein GhRPS6 and Its Role in Cotton Verticillium Wilt Resistance

Growth-induced physiological hypoxia correlates with growth deceleration during normal development

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