Regulation of Oncogenic Translation by the mTORC1/S6K1-IBTK-eIF4A1 Signaling Axis

מושגי ליבה

The mTORC1/S6K1 signaling pathway promotes sustained oncogenic translation by enhancing IBTK-mediated non-degradative ubiquitination of eIF4A1, a crucial subunit of the eIF4F complex.

תקציר

The content explores the role of the mTORC1/S6K1-IBTK-eIF4A1 signaling axis in regulating oncogenic translation and tumor cell growth. Key highlights:

1. IBTK, a substrate-binding adaptor of the Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with and promotes non-degradative ubiquitination of eIF4A1, a key component of the eIF4F translation initiation complex.

2. The mTORC1 and S6K1 kinases directly phosphorylate IBTK at multiple sites, which enhances the CRL3IBTK-mediated ubiquitination of eIF4A1 under nutrient-rich conditions.

3. IBTK-mediated eIF4A1 ubiquitination promotes cap-dependent translation initiation, nascent protein synthesis, oncogene expression, and tumor cell growth both in vitro and in vivo.

4. Depletion of IBTK reduces the expression of eIF4A1-regulated oncogenes, impairs neoplastic phenotypes in cancer cells, and sensitizes cells to eIF4A inhibitor-induced apoptosis.

5. Overexpression of IBTK correlates with poor survival in cervical cancer, highlighting its clinical relevance.

Overall, the study reveals a critical link between the mTORC1/S6K1 signaling pathway and the CRL3IBTK complex in regulating oncogenic translation, which represents a promising target for anti-cancer therapies.

סטטיסטיקה

Enhanced protein synthesis is a crucial molecular mechanism that allows cancer cells to survive, proliferate, metastasize, and develop resistance to anti-cancer treatments.
The mTORC1 signaling pathway plays a crucial role in promoting cell growth and anabolism by regulating various aspects of mRNA translation.
The Cullin 3-RING ubiquitin ligase (CRL3) complex can facilitate non-degradative ubiquitination, which can modulate protein activity, localization, or interaction.
IBTK, a substrate-binding adaptor of the CRL3 complex, has been implicated in promoting cell survival and tumor growth.

ציטוטים

"Enhanced protein synthesis is a crucial molecular mechanism that allows cancer cells to survive, proliferate, metastasize, and develop resistance to anti-cancer treatments."
"The mTORC1 signaling pathway plays a crucial role in promoting cell growth and anabolism while inhibiting catabolism."
"The Cullin 3-RING ubiquitin ligase (CRL3) complex plays a role in regulating various cellular processes, including cell division, differentiation, and signaling."
"IBTK, a substrate-binding adaptor of the CRL3 complex, has been implicated in promoting cell survival and tumor growth."

תובנות מפתח מזוקקות מ:

mTORC1/S6K1 signaling promotes sustained oncogenic translation through modulating CRL3IBTK-mediated non-degradative ubiquitination of eIF4A1

by Sun,H., Jiao... ב- www.biorxiv.org 09-29-2023

https://www.biorxiv.org/content/10.1101/2023.09.27.559872v2

שאלות מעמיקות

What other cellular processes or signaling pathways might the CRL3IBTK complex be involved in, beyond its role in regulating oncogenic translation?

The CRL3IBTK complex, in addition to its role in regulating oncogenic translation, may be involved in various other cellular processes and signaling pathways. One potential area of interest is the regulation of cell cycle progression and cell division. As a substrate-binding adaptor of the Cullin 3-RING ubiquitin ligase (CRL3) complex, IBTK could potentially target key cell cycle regulators for ubiquitination and degradation, thereby influencing cell cycle dynamics. Additionally, given its interaction with eIF2α, IBTK may play a role in modulating the integrated stress response and cellular adaptation to environmental stressors. Furthermore, the CRL3IBTK complex could be involved in the regulation of protein quality control mechanisms, such as ER-associated degradation (ERAD) or autophagy, by targeting specific substrates for ubiquitination and subsequent degradation. Overall, the CRL3IBTK complex likely participates in a wide range of cellular processes beyond oncogenic translation, highlighting its multifaceted role in cellular homeostasis.

How might the interplay between the mTORC1/S6K1 signaling and the CRL3IBTK complex be influenced by different cellular contexts or environmental conditions?

The interplay between the mTORC1/S6K1 signaling pathway and the CRL3IBTK complex could be influenced by various cellular contexts and environmental conditions. For instance, nutrient availability and cellular energy status play a crucial role in regulating mTORC1 activity. In nutrient-rich conditions, active mTORC1 can phosphorylate S6K1, which in turn phosphorylates IBTK, enhancing its activity in promoting eIF4A1 ubiquitination and oncogenic translation. Conversely, nutrient deprivation or cellular stress may inhibit mTORC1 signaling, leading to reduced phosphorylation of S6K1 and IBTK, thereby dampening the ubiquitination of eIF4A1 and suppressing oncogenic translation. Additionally, cellular signaling pathways activated in response to environmental cues, such as growth factors or stress stimuli, may modulate the crosstalk between mTORC1/S6K1 and the CRL3IBTK complex. These signaling pathways could converge on key nodes within the mTORC1/S6K1-IBTK-eIF4A1 axis, influencing its activity and downstream effects in a context-dependent manner.

Could the insights gained from this study on the mTORC1/S6K1-IBTK-eIF4A1 axis be leveraged to develop novel therapeutic strategies for other types of cancer beyond cervical cancer?

The insights gained from the study on the mTORC1/S6K1-IBTK-eIF4A1 axis have the potential to be leveraged for the development of novel therapeutic strategies for various types of cancer beyond cervical cancer. Targeting the mTORC1/S6K1-IBTK-eIF4A1 axis could be a promising approach for inhibiting oncogenic translation and suppressing tumor growth in different cancer types characterized by dysregulated protein synthesis. By identifying small molecules or inhibitors that disrupt the interaction between IBTK and eIF4A1, or that inhibit the phosphorylation of IBTK by mTORC1/S6K1, novel therapeutic agents could be developed to selectively target cancer cells dependent on enhanced protein synthesis. Additionally, the identification of downstream effectors of the mTORC1/S6K1-IBTK-eIF4A1 axis could lead to the discovery of new druggable targets for precision medicine approaches in cancer treatment. Overall, the findings from this study provide a foundation for exploring the therapeutic potential of targeting the mTORC1/S6K1-IBTK-eIF4A1 axis in a broader range of cancer types.