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mTORC1 and -2 Coordinate Transcriptional and Translational Reprogramming in Resistance to DNA Damage and Replicative Stress in Breast Cancer Cells.

Identifieur interne : 000684 ( Main/Exploration ); précédent : 000683; suivant : 000685

mTORC1 and -2 Coordinate Transcriptional and Translational Reprogramming in Resistance to DNA Damage and Replicative Stress in Breast Cancer Cells.

Auteurs : Deborah Silvera [États-Unis] ; Amanda Ernlund [États-Unis] ; Rezina Arju [États-Unis] ; Eileen Connolly [États-Unis] ; Viviana Volta [États-Unis] ; Jinhua Wang [États-Unis] ; Robert J. Schneider [États-Unis]

Source :

RBID : pubmed:27956700

Descripteurs français

English descriptors

Abstract

mTOR coordinates growth signals with metabolic pathways and protein synthesis and is hyperactivated in many human cancers. mTOR exists in two complexes: mTORC1, which stimulates protein, lipid, and ribosome biosynthesis, and mTORC2, which regulates cytoskeleton functions. While mTOR is known to be involved in the DNA damage response, little is actually known regarding the functions of mTORC1 compared to mTORC2 in this regard or the respective impacts on transcriptional versus translational regulation. We show that mTORC1 and mTORC2 are both required to enact DNA damage repair and cell survival, resulting in increased cancer cell survival during DNA damage. Together mTORC1 and -2 enact coordinated transcription and translation of protective cell cycle and DNA replication, recombination, and repair genes. This coordinated transcriptional-translational response to DNA damage was not impaired by rapalog inhibition of mTORC1 or independent inhibition of mTORC1 or mTORC2 but was blocked by inhibition of mTORC1/2. Only mTORC1/2 inhibition reversed cancer cell resistance to DNA damage and replicative stress and increased tumor cell killing and tumor control by DNA damage therapies in animal models. When combined with DNA damage, inhibition of mTORC1/2 blocked transcriptional induction more strongly than translation of DNA replication, survival, and DNA damage response mRNAs.

DOI: 10.1128/MCB.00577-16
PubMed: 27956700
PubMed Central: PMC5311240


Affiliations:


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Le document en format XML

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<term>Animals (MeSH)</term>
<term>Breast Neoplasms (genetics)</term>
<term>Breast Neoplasms (pathology)</term>
<term>Cell Cycle Checkpoints (genetics)</term>
<term>DNA (metabolism)</term>
<term>DNA Damage (genetics)</term>
<term>DNA Repair (genetics)</term>
<term>DNA Replication (genetics)</term>
<term>Female (MeSH)</term>
<term>G1 Phase (genetics)</term>
<term>Gene Expression Regulation, Neoplastic (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (MeSH)</term>
<term>Mechanistic Target of Rapamycin Complex 2 (MeSH)</term>
<term>Mice (MeSH)</term>
<term>Multiprotein Complexes (antagonists & inhibitors)</term>
<term>Multiprotein Complexes (metabolism)</term>
<term>Protein Biosynthesis (MeSH)</term>
<term>RNA, Messenger (genetics)</term>
<term>RNA, Messenger (metabolism)</term>
<term>Real-Time Polymerase Chain Reaction (MeSH)</term>
<term>S Phase (genetics)</term>
<term>Stress, Physiological (genetics)</term>
<term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term>
<term>TOR Serine-Threonine Kinases (metabolism)</term>
<term>Transcription, Genetic (MeSH)</term>
<term>Xenograft Model Antitumor Assays (MeSH)</term>
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<term>ADN (métabolisme)</term>
<term>ARN messager (génétique)</term>
<term>ARN messager (métabolisme)</term>
<term>Altération de l'ADN (génétique)</term>
<term>Animaux (MeSH)</term>
<term>Biosynthèse des protéines (MeSH)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (MeSH)</term>
<term>Complexe-2 cible mécanistique de la rapamycine (MeSH)</term>
<term>Complexes multiprotéiques (antagonistes et inhibiteurs)</term>
<term>Complexes multiprotéiques (métabolisme)</term>
<term>Femelle (MeSH)</term>
<term>Humains (MeSH)</term>
<term>Phase G1 (génétique)</term>
<term>Phase S (génétique)</term>
<term>Points de contrôle du cycle cellulaire (génétique)</term>
<term>Réaction de polymérisation en chaine en temps réel (MeSH)</term>
<term>Régulation de l'expression des gènes tumoraux (MeSH)</term>
<term>Réparation de l'ADN (génétique)</term>
<term>Réplication de l'ADN (génétique)</term>
<term>Souris (MeSH)</term>
<term>Stress physiologique (génétique)</term>
<term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term>
<term>Sérine-thréonine kinases TOR (métabolisme)</term>
<term>Tests d'activité antitumorale sur modèle de xénogreffe (MeSH)</term>
<term>Transcription génétique (MeSH)</term>
<term>Tumeurs du sein (anatomopathologie)</term>
<term>Tumeurs du sein (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en">
<term>Multiprotein Complexes</term>
<term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en">
<term>RNA, Messenger</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en">
<term>DNA</term>
<term>Multiprotein Complexes</term>
<term>RNA, Messenger</term>
<term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr">
<term>Tumeurs du sein</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr">
<term>Complexes multiprotéiques</term>
<term>Sérine-thréonine kinases TOR</term>
</keywords>
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<term>Breast Neoplasms</term>
<term>Cell Cycle Checkpoints</term>
<term>DNA Damage</term>
<term>DNA Repair</term>
<term>DNA Replication</term>
<term>G1 Phase</term>
<term>S Phase</term>
<term>Stress, Physiological</term>
</keywords>
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<term>ARN messager</term>
<term>Altération de l'ADN</term>
<term>Phase G1</term>
<term>Phase S</term>
<term>Points de contrôle du cycle cellulaire</term>
<term>Réparation de l'ADN</term>
<term>Réplication de l'ADN</term>
<term>Stress physiologique</term>
<term>Tumeurs du sein</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>ADN</term>
<term>ARN messager</term>
<term>Complexes multiprotéiques</term>
<term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en">
<term>Breast Neoplasms</term>
</keywords>
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<term>Animals</term>
<term>Female</term>
<term>Gene Expression Regulation, Neoplastic</term>
<term>Humans</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Mechanistic Target of Rapamycin Complex 2</term>
<term>Mice</term>
<term>Protein Biosynthesis</term>
<term>Real-Time Polymerase Chain Reaction</term>
<term>Transcription, Genetic</term>
<term>Xenograft Model Antitumor Assays</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Animaux</term>
<term>Biosynthèse des protéines</term>
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Complexe-2 cible mécanistique de la rapamycine</term>
<term>Femelle</term>
<term>Humains</term>
<term>Réaction de polymérisation en chaine en temps réel</term>
<term>Régulation de l'expression des gènes tumoraux</term>
<term>Souris</term>
<term>Tests d'activité antitumorale sur modèle de xénogreffe</term>
<term>Transcription génétique</term>
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<front>
<div type="abstract" xml:lang="en">mTOR coordinates growth signals with metabolic pathways and protein synthesis and is hyperactivated in many human cancers. mTOR exists in two complexes: mTORC1, which stimulates protein, lipid, and ribosome biosynthesis, and mTORC2, which regulates cytoskeleton functions. While mTOR is known to be involved in the DNA damage response, little is actually known regarding the functions of mTORC1 compared to mTORC2 in this regard or the respective impacts on transcriptional versus translational regulation. We show that mTORC1 and mTORC2 are both required to enact DNA damage repair and cell survival, resulting in increased cancer cell survival during DNA damage. Together mTORC1 and -2 enact coordinated transcription and translation of protective cell cycle and DNA replication, recombination, and repair genes. This coordinated transcriptional-translational response to DNA damage was not impaired by rapalog inhibition of mTORC1 or independent inhibition of mTORC1 or mTORC2 but was blocked by inhibition of mTORC1/2. Only mTORC1/2 inhibition reversed cancer cell resistance to DNA damage and replicative stress and increased tumor cell killing and tumor control by DNA damage therapies in animal models. When combined with DNA damage, inhibition of mTORC1/2 blocked transcriptional induction more strongly than translation of DNA replication, survival, and DNA damage response mRNAs.</div>
</front>
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<AbstractText>mTOR coordinates growth signals with metabolic pathways and protein synthesis and is hyperactivated in many human cancers. mTOR exists in two complexes: mTORC1, which stimulates protein, lipid, and ribosome biosynthesis, and mTORC2, which regulates cytoskeleton functions. While mTOR is known to be involved in the DNA damage response, little is actually known regarding the functions of mTORC1 compared to mTORC2 in this regard or the respective impacts on transcriptional versus translational regulation. We show that mTORC1 and mTORC2 are both required to enact DNA damage repair and cell survival, resulting in increased cancer cell survival during DNA damage. Together mTORC1 and -2 enact coordinated transcription and translation of protective cell cycle and DNA replication, recombination, and repair genes. This coordinated transcriptional-translational response to DNA damage was not impaired by rapalog inhibition of mTORC1 or independent inhibition of mTORC1 or mTORC2 but was blocked by inhibition of mTORC1/2. Only mTORC1/2 inhibition reversed cancer cell resistance to DNA damage and replicative stress and increased tumor cell killing and tumor control by DNA damage therapies in animal models. When combined with DNA damage, inhibition of mTORC1/2 blocked transcriptional induction more strongly than translation of DNA replication, survival, and DNA damage response mRNAs.</AbstractText>
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<GrantID>P30 CA016087</GrantID>
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<Country>United States</Country>
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<Grant>
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<Grant>
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