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Synthetic human cell fate regulation by protein-driven RNA switches.

Saito H, Fujita Y, Kashida S, Hayashi K, Inoue T - Nat Commun (2011)

Bottom Line: Combined use of the switches demonstrates that a specific protein can simultaneously repress and activate the translation of two different mRNAs: one protein achieves both up- and downregulation of two different proteins/pathways.A genome-encoded protein fused to L7Ae controlled apoptosis in both directions (death or survival) depending on its cellular expression.The method has potential for curing cellular defects or improving the intracellular production of useful molecules by bypassing or rewiring intrinsic signal networks.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratory of Gene Biodynamics, Graduate School of Biostudies, Kyoto University, Oiwake-cho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan. [2] International Cooperative Research Project, Japan Science and Technology Agency, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan. [3] The Hakubi Center, Kyoto University, Oiwake-cho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan.

ABSTRACT
Understanding how to control cell fate is crucial in biology, medical science and engineering. In this study, we introduce a method that uses an intracellular protein as a trigger for regulating human cell fate. The ON/OFF translational switches, composed of an intracellular protein L7Ae and its binding RNA motif, regulate the expression of a desired target protein and control two distinct apoptosis pathways in target human cells. Combined use of the switches demonstrates that a specific protein can simultaneously repress and activate the translation of two different mRNAs: one protein achieves both up- and downregulation of two different proteins/pathways. A genome-encoded protein fused to L7Ae controlled apoptosis in both directions (death or survival) depending on its cellular expression. The method has potential for curing cellular defects or improving the intracellular production of useful molecules by bypassing or rewiring intrinsic signal networks.

No MeSH data available.


Schematic diagram for regulation of cell death by protein-driven RNA ON/OFF switches.(a) Schematic representation of the outcome of this study. A protein encoded in genome drives translational switches and regulates intrinsic apoptosis signal cascade to control cell fate (death or survival). (b) Schematic diagram of the circuit connected to intrinsic apoptosis signal cascades regulated by the switches. Two distinct (mitochondria dependent and independent) apoptosis pathways controlled by L7Ae. L7Ae strictly regulates the production of apoptotic regulatory proteins (that is, Bcl-xL, Bim, FADD) involved in the complex intrinsic apoptosis signal cascades. Several steps of signal-transduction cascades and activation of a set of caspases are required to determine cell death.
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f1: Schematic diagram for regulation of cell death by protein-driven RNA ON/OFF switches.(a) Schematic representation of the outcome of this study. A protein encoded in genome drives translational switches and regulates intrinsic apoptosis signal cascade to control cell fate (death or survival). (b) Schematic diagram of the circuit connected to intrinsic apoptosis signal cascades regulated by the switches. Two distinct (mitochondria dependent and independent) apoptosis pathways controlled by L7Ae. L7Ae strictly regulates the production of apoptotic regulatory proteins (that is, Bcl-xL, Bim, FADD) involved in the complex intrinsic apoptosis signal cascades. Several steps of signal-transduction cascades and activation of a set of caspases are required to determine cell death.

Mentions: A system that allows an endogenously expressed molecule such as a protein to control the expression level of a target gene would be especially advantageous. A method in which a specific protein produced in a cell can directly and quantitatively regulate the production of target protein(s) could be used to bypass or rewire intrinsic signalling networks and to construct novel cascades or feedback circuits for controlling cell functions (Fig. 1a)1718.


Synthetic human cell fate regulation by protein-driven RNA switches.

Saito H, Fujita Y, Kashida S, Hayashi K, Inoue T - Nat Commun (2011)

Schematic diagram for regulation of cell death by protein-driven RNA ON/OFF switches.(a) Schematic representation of the outcome of this study. A protein encoded in genome drives translational switches and regulates intrinsic apoptosis signal cascade to control cell fate (death or survival). (b) Schematic diagram of the circuit connected to intrinsic apoptosis signal cascades regulated by the switches. Two distinct (mitochondria dependent and independent) apoptosis pathways controlled by L7Ae. L7Ae strictly regulates the production of apoptotic regulatory proteins (that is, Bcl-xL, Bim, FADD) involved in the complex intrinsic apoptosis signal cascades. Several steps of signal-transduction cascades and activation of a set of caspases are required to determine cell death.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105309&req=5

f1: Schematic diagram for regulation of cell death by protein-driven RNA ON/OFF switches.(a) Schematic representation of the outcome of this study. A protein encoded in genome drives translational switches and regulates intrinsic apoptosis signal cascade to control cell fate (death or survival). (b) Schematic diagram of the circuit connected to intrinsic apoptosis signal cascades regulated by the switches. Two distinct (mitochondria dependent and independent) apoptosis pathways controlled by L7Ae. L7Ae strictly regulates the production of apoptotic regulatory proteins (that is, Bcl-xL, Bim, FADD) involved in the complex intrinsic apoptosis signal cascades. Several steps of signal-transduction cascades and activation of a set of caspases are required to determine cell death.
Mentions: A system that allows an endogenously expressed molecule such as a protein to control the expression level of a target gene would be especially advantageous. A method in which a specific protein produced in a cell can directly and quantitatively regulate the production of target protein(s) could be used to bypass or rewire intrinsic signalling networks and to construct novel cascades or feedback circuits for controlling cell functions (Fig. 1a)1718.

Bottom Line: Combined use of the switches demonstrates that a specific protein can simultaneously repress and activate the translation of two different mRNAs: one protein achieves both up- and downregulation of two different proteins/pathways.A genome-encoded protein fused to L7Ae controlled apoptosis in both directions (death or survival) depending on its cellular expression.The method has potential for curing cellular defects or improving the intracellular production of useful molecules by bypassing or rewiring intrinsic signal networks.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratory of Gene Biodynamics, Graduate School of Biostudies, Kyoto University, Oiwake-cho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan. [2] International Cooperative Research Project, Japan Science and Technology Agency, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan. [3] The Hakubi Center, Kyoto University, Oiwake-cho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan.

ABSTRACT
Understanding how to control cell fate is crucial in biology, medical science and engineering. In this study, we introduce a method that uses an intracellular protein as a trigger for regulating human cell fate. The ON/OFF translational switches, composed of an intracellular protein L7Ae and its binding RNA motif, regulate the expression of a desired target protein and control two distinct apoptosis pathways in target human cells. Combined use of the switches demonstrates that a specific protein can simultaneously repress and activate the translation of two different mRNAs: one protein achieves both up- and downregulation of two different proteins/pathways. A genome-encoded protein fused to L7Ae controlled apoptosis in both directions (death or survival) depending on its cellular expression. The method has potential for curing cellular defects or improving the intracellular production of useful molecules by bypassing or rewiring intrinsic signal networks.

No MeSH data available.