Repression of p15INK4b expression by Myc through association with Miz-1.

P Staller; K Peukert; A Kiermaier; J Seoane; J Lukas; H Karsunky; T Möröy; J Bartek; J Massagué; F Hänel; M Eilers

doi:10.1038/35070076

Repression of p15INK4b expression by Myc through association with Miz-1.

P Staller, K Peukert, A Kiermaier, J Seoane, J Lukas, H Karsunky, T Möröy, J Bartek, J Massagué, F Hänel, M Eilers

431 Citations (Scopus)

Abstract

Deregulated expression of c-myc can induce cell proliferation in established cell lines and in primary mouse embryonic fibroblasts (MEFs), through a combination of both transcriptional activation and repression by Myc. Here we show that a Myc-associated transcription factor, Miz-1, arrests cells in G1 phase and inhibits cyclin D-associated kinase activity. Miz-1 upregulates expression of the cyclin-dependent kinases (CDK) inhibitor p15INK4b by binding to the initiator element of the p15INK4b promoter. Myc and Max form a complex with Miz-1 at the p15 initiator and inhibit transcriptional activation by Miz-1. Expression of Myc in primary cells inhibits the accumulation of p15INK4b that is associated with cellular senescence; conversely, deletion of c-myc in an established cell line activates p15INK4b expression. Alleles of c-myc that are unable to bind to Miz-1 fail to inhibit accumulation of p15INK4b messenger RNA in primary cells and are, as a consequence, deficient in immortalization.

Original language	English
Journal	Nature Cell Biology
Volume	3
Issue number	4
Pages (from-to)	392-9
Number of pages	7
ISSN	1465-7392
DOIs	https://doi.org/10.1038/35070076
Publication status	Published - 2001

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@article{33dee6d051a611dd8d9f000ea68e967b,

title = "Repression of p15INK4b expression by Myc through association with Miz-1.",

abstract = "Deregulated expression of c-myc can induce cell proliferation in established cell lines and in primary mouse embryonic fibroblasts (MEFs), through a combination of both transcriptional activation and repression by Myc. Here we show that a Myc-associated transcription factor, Miz-1, arrests cells in G1 phase and inhibits cyclin D-associated kinase activity. Miz-1 upregulates expression of the cyclin-dependent kinases (CDK) inhibitor p15INK4b by binding to the initiator element of the p15INK4b promoter. Myc and Max form a complex with Miz-1 at the p15 initiator and inhibit transcriptional activation by Miz-1. Expression of Myc in primary cells inhibits the accumulation of p15INK4b that is associated with cellular senescence; conversely, deletion of c-myc in an established cell line activates p15INK4b expression. Alleles of c-myc that are unable to bind to Miz-1 fail to inhibit accumulation of p15INK4b messenger RNA in primary cells and are, as a consequence, deficient in immortalization.",

author = "P Staller and K Peukert and A Kiermaier and J Seoane and J Lukas and H Karsunky and T M{\"o}r{\"o}y and J Bartek and J Massagu{\'e} and F H{\"a}nel and M Eilers",

note = "Keywords: 3T3 Cells; Animals; Carrier Proteins; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; DNA-Binding Proteins; Gene Expression Regulation; Hela Cells; Humans; Kruppel-Like Transcription Factors; Mice; Nuclear Proteins; Promoter Regions (Genetics); Proto-Oncogene Proteins c-myc; Rats; Recombinant Fusion Proteins; Trans-Activators; Transcription Factors; Tumor Suppressor Proteins; Zinc Fingers",

year = "2001",

doi = "10.1038/35070076",

language = "English",

volume = "3",

pages = "392--9",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "nature publishing group",

number = "4",

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T1 - Repression of p15INK4b expression by Myc through association with Miz-1.

AU - Staller, P

AU - Peukert, K

AU - Kiermaier, A

AU - Seoane, J

AU - Lukas, J

AU - Karsunky, H

AU - Möröy, T

AU - Bartek, J

AU - Massagué, J

AU - Hänel, F

AU - Eilers, M

N1 - Keywords: 3T3 Cells; Animals; Carrier Proteins; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; DNA-Binding Proteins; Gene Expression Regulation; Hela Cells; Humans; Kruppel-Like Transcription Factors; Mice; Nuclear Proteins; Promoter Regions (Genetics); Proto-Oncogene Proteins c-myc; Rats; Recombinant Fusion Proteins; Trans-Activators; Transcription Factors; Tumor Suppressor Proteins; Zinc Fingers

PY - 2001

Y1 - 2001

N2 - Deregulated expression of c-myc can induce cell proliferation in established cell lines and in primary mouse embryonic fibroblasts (MEFs), through a combination of both transcriptional activation and repression by Myc. Here we show that a Myc-associated transcription factor, Miz-1, arrests cells in G1 phase and inhibits cyclin D-associated kinase activity. Miz-1 upregulates expression of the cyclin-dependent kinases (CDK) inhibitor p15INK4b by binding to the initiator element of the p15INK4b promoter. Myc and Max form a complex with Miz-1 at the p15 initiator and inhibit transcriptional activation by Miz-1. Expression of Myc in primary cells inhibits the accumulation of p15INK4b that is associated with cellular senescence; conversely, deletion of c-myc in an established cell line activates p15INK4b expression. Alleles of c-myc that are unable to bind to Miz-1 fail to inhibit accumulation of p15INK4b messenger RNA in primary cells and are, as a consequence, deficient in immortalization.

AB - Deregulated expression of c-myc can induce cell proliferation in established cell lines and in primary mouse embryonic fibroblasts (MEFs), through a combination of both transcriptional activation and repression by Myc. Here we show that a Myc-associated transcription factor, Miz-1, arrests cells in G1 phase and inhibits cyclin D-associated kinase activity. Miz-1 upregulates expression of the cyclin-dependent kinases (CDK) inhibitor p15INK4b by binding to the initiator element of the p15INK4b promoter. Myc and Max form a complex with Miz-1 at the p15 initiator and inhibit transcriptional activation by Miz-1. Expression of Myc in primary cells inhibits the accumulation of p15INK4b that is associated with cellular senescence; conversely, deletion of c-myc in an established cell line activates p15INK4b expression. Alleles of c-myc that are unable to bind to Miz-1 fail to inhibit accumulation of p15INK4b messenger RNA in primary cells and are, as a consequence, deficient in immortalization.

U2 - 10.1038/35070076

DO - 10.1038/35070076

M3 - Journal article

C2 - 11283613

SN - 1465-7392

VL - 3

SP - 392

EP - 399

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 4

ER -

Repression of p15INK4b expression by Myc through association with Miz-1.

Abstract

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