MNK1 and EIF4E are downstream effectors of MEKs in the regulation of the nuclear export of HDM2 mRNA
MNK1 and EIF4E are downstream effectors of MEKs in the regulation of the nuclear export of HDM2 mRNA
Regulation of the synthesis, function and degradation of HDM2 (Mdm2 in mouse) plays a key role in controlling the abundance and activity of the transcription factor p53, with consequent implications for the proliferation and survival of normal and cancer cells. We have previously identified the regulation of export of HDM2 mRNA from the nucleus as a novel point of control of HDM2 synthesis. This process is dependent on the activity of the growth factor-regulated MAP-kinase kinases ( MEKs). Here, we provide evidence that the eIF4E kinase MNK1 is a key downstream effector of MEKs in this regulatory pathway. We show that HDM2 mRNA export in breast cancer cells is promoted by overexpressed eIF4E in a MEK- and MNK1-dependent manner, and inhibition of MNK1 suppresses endogenous HDM2 mRNA export pathways. This MNK1- and eIF4E-dependent HDM2 regulation occurs through sequences in the 30 untranslated region of HDM2 mRNA, and consequently HDM2 mRNA transcripts from both the constitutive P1 and inducible P2 promoters are regulated by this pathway. eIF4E is a known oncogene that is overexpressed in human tumours, including the majority of breast cancers. This pathway, therefore, may play an important role in the dysregulation of HDM2 oncoprotein expression that occurs in many human tumours.
survival, eif4e, mrna export, cancer, p53, protein, activation, expression, translation initiation, mdm2, p53 pathway, negative regulation, initiation-factor eif4e, breast cancer, single nucleotide polymorphism, mouse, gene-expression, transport
1645-1649
Phillips, A.
3f6d00b5-fb3c-423b-976d-83f22a2dc47b
Blaydes, J.P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
March 2008
Phillips, A.
3f6d00b5-fb3c-423b-976d-83f22a2dc47b
Blaydes, J.P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Phillips, A. and Blaydes, J.P.
(2008)
MNK1 and EIF4E are downstream effectors of MEKs in the regulation of the nuclear export of HDM2 mRNA.
Oncogene, 27 (11), .
(doi:10.1038/sj.onc.1210785).
Abstract
Regulation of the synthesis, function and degradation of HDM2 (Mdm2 in mouse) plays a key role in controlling the abundance and activity of the transcription factor p53, with consequent implications for the proliferation and survival of normal and cancer cells. We have previously identified the regulation of export of HDM2 mRNA from the nucleus as a novel point of control of HDM2 synthesis. This process is dependent on the activity of the growth factor-regulated MAP-kinase kinases ( MEKs). Here, we provide evidence that the eIF4E kinase MNK1 is a key downstream effector of MEKs in this regulatory pathway. We show that HDM2 mRNA export in breast cancer cells is promoted by overexpressed eIF4E in a MEK- and MNK1-dependent manner, and inhibition of MNK1 suppresses endogenous HDM2 mRNA export pathways. This MNK1- and eIF4E-dependent HDM2 regulation occurs through sequences in the 30 untranslated region of HDM2 mRNA, and consequently HDM2 mRNA transcripts from both the constitutive P1 and inducible P2 promoters are regulated by this pathway. eIF4E is a known oncogene that is overexpressed in human tumours, including the majority of breast cancers. This pathway, therefore, may play an important role in the dysregulation of HDM2 oncoprotein expression that occurs in many human tumours.
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e-pub ahead of print date: 10 September 2007
Published date: March 2008
Keywords:
survival, eif4e, mrna export, cancer, p53, protein, activation, expression, translation initiation, mdm2, p53 pathway, negative regulation, initiation-factor eif4e, breast cancer, single nucleotide polymorphism, mouse, gene-expression, transport
Organisations:
Cancer Sciences
Identifiers
Local EPrints ID: 62881
URI: http://eprints.soton.ac.uk/id/eprint/62881
ISSN: 0950-9232
PURE UUID: 64ca381a-5e13-4caf-adb8-0fc54765f2e9
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Date deposited: 09 Sep 2008
Last modified: 16 Mar 2024 03:18
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Author:
A. Phillips
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