Rit GTPase regulates a p38 MAPK-dependent neuronal survival pathway

Weikang Cai; Jennifer L. Rudolph; Tomoko Sengoku; Douglas A. Andres

doi:10.1016/j.neulet.2012.10.036

Rit GTPase regulates a p38 MAPK-dependent neuronal survival pathway

Weikang Cai
, Jennifer L. Rudolph
, Tomoko Sengoku
, Douglas A. Andres

Producción científica: Article › revisión exhaustiva

16 Citas (Scopus)

Resumen

Rit, along with Rin and Drosophila Ric, comprises the Rit subfamily of Ras-related small GTPases. Although the cellular functions of many Ras family GTPases are well established, the physiological significance of Rit remains poorly understood. Loss of Rit sensitizes multiple mammalian cell lines and mouse embryonic fibroblasts (MEFs) derived from Rit^-/- mice to oxidative stress-mediated apoptosis. However, whether Rit-mediated pro-survival signaling extends to other cell types, particularly neurons, is presently unknown. Here, to examine these issues we generated a transgenic mouse overexpressing constitutively active Rit (Rit^Q79L) exclusively in neurons, under control of the Synapsin I promoter. Active Rit-expressing hippocampal neurons display a dramatic increase in oxidative stress resistance. Moreover, pharmacological inhibitor studies demonstrate that p38 MAPK, rather than a MEK/ERK signaling cascade, is required for Rit-mediated protection. Together, the present studies identify a critical role for the Rit-p38 MAPK signaling cascade in promoting hippocampal neuron survival following oxidative stress.

Idioma original	English
Páginas (desde-hasta)	125-130
Número de páginas	6
Publicación	Neuroscience Letters
Volumen	531
N.º	2
DOI	https://doi.org/10.1016/j.neulet.2012.10.036
Estado	Published - dic 7 2012

Nota bibliográfica

Funding Information:
We thank Drs. G.-X. Shi, and C. Moncman for helpful discussions. This work was supported by Public Health Service grant NS045103 from the National Institute of Neurological Disorders and Stroke (D.A.A.) and in part by NIH grant P20GM103486 from the National Institute of General Medical Sciences , its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS.

Financiación

We thank Drs. G.-X. Shi, and C. Moncman for helpful discussions. This work was supported by Public Health Service grant NS045103 from the National Institute of Neurological Disorders and Stroke (D.A.A.) and in part by NIH grant P20GM103486 from the National Institute of General Medical Sciences , its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS.

Financiadores	Número del financiador
National Institutes of Health (NIH)
National Institute of General Medical Sciences	P20GM103486
National Institute of Neurological Disorders and Stroke	R01NS045103
U.S. Public Health Service	NS045103

ASJC Scopus subject areas

General Neuroscience

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title = "Rit GTPase regulates a p38 MAPK-dependent neuronal survival pathway",

abstract = "Rit, along with Rin and Drosophila Ric, comprises the Rit subfamily of Ras-related small GTPases. Although the cellular functions of many Ras family GTPases are well established, the physiological significance of Rit remains poorly understood. Loss of Rit sensitizes multiple mammalian cell lines and mouse embryonic fibroblasts (MEFs) derived from Rit-/- mice to oxidative stress-mediated apoptosis. However, whether Rit-mediated pro-survival signaling extends to other cell types, particularly neurons, is presently unknown. Here, to examine these issues we generated a transgenic mouse overexpressing constitutively active Rit (RitQ79L) exclusively in neurons, under control of the Synapsin I promoter. Active Rit-expressing hippocampal neurons display a dramatic increase in oxidative stress resistance. Moreover, pharmacological inhibitor studies demonstrate that p38 MAPK, rather than a MEK/ERK signaling cascade, is required for Rit-mediated protection. Together, the present studies identify a critical role for the Rit-p38 MAPK signaling cascade in promoting hippocampal neuron survival following oxidative stress.",

keywords = "Hippocampal neuron, Ras GTPase, Reactive oxygen species (ROS), Stress, Survival",

author = "Weikang Cai and Rudolph, \{Jennifer L.\} and Tomoko Sengoku and Andres, \{Douglas A.\}",

note = "Funding Information: We thank Drs. G.-X. Shi, and C. Moncman for helpful discussions. This work was supported by Public Health Service grant NS045103 from the National Institute of Neurological Disorders and Stroke (D.A.A.) and in part by NIH grant P20GM103486 from the National Institute of General Medical Sciences , its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS.",

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doi = "10.1016/j.neulet.2012.10.036",

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AU - Cai, Weikang

AU - Rudolph, Jennifer L.

AU - Sengoku, Tomoko

AU - Andres, Douglas A.

N1 - Funding Information: We thank Drs. G.-X. Shi, and C. Moncman for helpful discussions. This work was supported by Public Health Service grant NS045103 from the National Institute of Neurological Disorders and Stroke (D.A.A.) and in part by NIH grant P20GM103486 from the National Institute of General Medical Sciences , its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS.

PY - 2012/12/7

Y1 - 2012/12/7

N2 - Rit, along with Rin and Drosophila Ric, comprises the Rit subfamily of Ras-related small GTPases. Although the cellular functions of many Ras family GTPases are well established, the physiological significance of Rit remains poorly understood. Loss of Rit sensitizes multiple mammalian cell lines and mouse embryonic fibroblasts (MEFs) derived from Rit-/- mice to oxidative stress-mediated apoptosis. However, whether Rit-mediated pro-survival signaling extends to other cell types, particularly neurons, is presently unknown. Here, to examine these issues we generated a transgenic mouse overexpressing constitutively active Rit (RitQ79L) exclusively in neurons, under control of the Synapsin I promoter. Active Rit-expressing hippocampal neurons display a dramatic increase in oxidative stress resistance. Moreover, pharmacological inhibitor studies demonstrate that p38 MAPK, rather than a MEK/ERK signaling cascade, is required for Rit-mediated protection. Together, the present studies identify a critical role for the Rit-p38 MAPK signaling cascade in promoting hippocampal neuron survival following oxidative stress.

AB - Rit, along with Rin and Drosophila Ric, comprises the Rit subfamily of Ras-related small GTPases. Although the cellular functions of many Ras family GTPases are well established, the physiological significance of Rit remains poorly understood. Loss of Rit sensitizes multiple mammalian cell lines and mouse embryonic fibroblasts (MEFs) derived from Rit-/- mice to oxidative stress-mediated apoptosis. However, whether Rit-mediated pro-survival signaling extends to other cell types, particularly neurons, is presently unknown. Here, to examine these issues we generated a transgenic mouse overexpressing constitutively active Rit (RitQ79L) exclusively in neurons, under control of the Synapsin I promoter. Active Rit-expressing hippocampal neurons display a dramatic increase in oxidative stress resistance. Moreover, pharmacological inhibitor studies demonstrate that p38 MAPK, rather than a MEK/ERK signaling cascade, is required for Rit-mediated protection. Together, the present studies identify a critical role for the Rit-p38 MAPK signaling cascade in promoting hippocampal neuron survival following oxidative stress.

KW - Hippocampal neuron

KW - Ras GTPase

KW - Reactive oxygen species (ROS)

KW - Stress

KW - Survival

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Rit GTPase regulates a p38 MAPK-dependent neuronal survival pathway

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ASJC Scopus subject areas

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