Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression domain of the Myc antagonist Mxi1

Govinda Rao, Leila Alland, Peter Guida, Nicole Schreiber-Agus, Ken Chen, Lynda Chin, Julie M. Rochelle, Michael F Seldin, Arthur I. Skoultchi, Ronald A. DePinho

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Mxi1 is a basic region helix-loop-helix leucine zipper (bHLH/LZ) protein that, in association with Max, antagonizes Myc oncogenic activities. A possible mechanistic basis for Mxi1-mediated repression was provided by the recent demonstration that the repressive potential of Mxi1 correlates with its ability to physically associate with mSin3B, one of two mammalian homologues of the yeast transcriptional repressor SIN3. Here, we sought to characterize more fully the physical properties of the second homologue, mSin3A and to determine whether the recruitment of mSin3A by Mxi1 is indeed required for anti-Myc activity. Transient transfection of mammalian cells showed that the mSin3A protein can associate with the strong repressive isoform of Mxi1 (Mxi1-SR) and that, like other Myc superfamily members, both mSin3A and Mxi1-SR localize to the nucleus. From a developmental standpoint, a comparative analysis of Myc, Mxi1-SR and Sin3A expression during postnatal mouse development and in differentiating mouse erythroleukemia (MEL) cells revealed that dramatic and reciprocal changes in Myc and Mxi1-SR mRNA levels are accompanied by minimal stage-specific changes in mSin3A gene expression. This constant expression profile, coupled with the observation that over-expression of mSin3A does not augment the anti-Myc activity of Mxi1-SR in the rat embryo fibroblast (REF) transformation assay, suggests that mSin3A is not a limiting factor in the regulation of Myc superfamily function. Finally, a mSin3A-Mxi1 fusion protein, in which the amino terminal mSin3-interacting domain of Mxi1-SR was replaced with the full-length mSin3A, exhibited a level of repression activity equivalent to, or greater than, the level of repression obtained with Mxi1-SR. Taken together, these observations directly demonstrate that the amino-terminal repression domain of Mxi1-SR functions solely to recruit mSin3A and possibly other proteins like mSin3A and this association is necessary for the anti-Myc activity of Mxi1-SR.

Original languageEnglish (US)
Pages (from-to)1165-1172
Number of pages8
JournalOncogene
Volume12
Issue number5
StatePublished - 1996
Externally publishedYes

Fingerprint

Proteins
Leucine Zippers
Leukemia, Erythroblastic, Acute
Transfection
Protein Isoforms
Embryonic Structures
Fibroblasts
Yeasts
Gene Expression
Messenger RNA

Keywords

  • Cotransformation
  • mSin3A
  • Mxi1
  • Myc
  • PAH domain
  • Repression

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Rao, G., Alland, L., Guida, P., Schreiber-Agus, N., Chen, K., Chin, L., ... DePinho, R. A. (1996). Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression domain of the Myc antagonist Mxi1. Oncogene, 12(5), 1165-1172.

Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression domain of the Myc antagonist Mxi1. / Rao, Govinda; Alland, Leila; Guida, Peter; Schreiber-Agus, Nicole; Chen, Ken; Chin, Lynda; Rochelle, Julie M.; Seldin, Michael F; Skoultchi, Arthur I.; DePinho, Ronald A.

In: Oncogene, Vol. 12, No. 5, 1996, p. 1165-1172.

Research output: Contribution to journalArticle

Rao, G, Alland, L, Guida, P, Schreiber-Agus, N, Chen, K, Chin, L, Rochelle, JM, Seldin, MF, Skoultchi, AI & DePinho, RA 1996, 'Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression domain of the Myc antagonist Mxi1', Oncogene, vol. 12, no. 5, pp. 1165-1172.
Rao G, Alland L, Guida P, Schreiber-Agus N, Chen K, Chin L et al. Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression domain of the Myc antagonist Mxi1. Oncogene. 1996;12(5):1165-1172.
Rao, Govinda ; Alland, Leila ; Guida, Peter ; Schreiber-Agus, Nicole ; Chen, Ken ; Chin, Lynda ; Rochelle, Julie M. ; Seldin, Michael F ; Skoultchi, Arthur I. ; DePinho, Ronald A. / Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression domain of the Myc antagonist Mxi1. In: Oncogene. 1996 ; Vol. 12, No. 5. pp. 1165-1172.
@article{183876201d8149f9bfaef87af0bd4c1a,
title = "Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression domain of the Myc antagonist Mxi1",
abstract = "Mxi1 is a basic region helix-loop-helix leucine zipper (bHLH/LZ) protein that, in association with Max, antagonizes Myc oncogenic activities. A possible mechanistic basis for Mxi1-mediated repression was provided by the recent demonstration that the repressive potential of Mxi1 correlates with its ability to physically associate with mSin3B, one of two mammalian homologues of the yeast transcriptional repressor SIN3. Here, we sought to characterize more fully the physical properties of the second homologue, mSin3A and to determine whether the recruitment of mSin3A by Mxi1 is indeed required for anti-Myc activity. Transient transfection of mammalian cells showed that the mSin3A protein can associate with the strong repressive isoform of Mxi1 (Mxi1-SR) and that, like other Myc superfamily members, both mSin3A and Mxi1-SR localize to the nucleus. From a developmental standpoint, a comparative analysis of Myc, Mxi1-SR and Sin3A expression during postnatal mouse development and in differentiating mouse erythroleukemia (MEL) cells revealed that dramatic and reciprocal changes in Myc and Mxi1-SR mRNA levels are accompanied by minimal stage-specific changes in mSin3A gene expression. This constant expression profile, coupled with the observation that over-expression of mSin3A does not augment the anti-Myc activity of Mxi1-SR in the rat embryo fibroblast (REF) transformation assay, suggests that mSin3A is not a limiting factor in the regulation of Myc superfamily function. Finally, a mSin3A-Mxi1 fusion protein, in which the amino terminal mSin3-interacting domain of Mxi1-SR was replaced with the full-length mSin3A, exhibited a level of repression activity equivalent to, or greater than, the level of repression obtained with Mxi1-SR. Taken together, these observations directly demonstrate that the amino-terminal repression domain of Mxi1-SR functions solely to recruit mSin3A and possibly other proteins like mSin3A and this association is necessary for the anti-Myc activity of Mxi1-SR.",
keywords = "Cotransformation, mSin3A, Mxi1, Myc, PAH domain, Repression",
author = "Govinda Rao and Leila Alland and Peter Guida and Nicole Schreiber-Agus and Ken Chen and Lynda Chin and Rochelle, {Julie M.} and Seldin, {Michael F} and Skoultchi, {Arthur I.} and DePinho, {Ronald A.}",
year = "1996",
language = "English (US)",
volume = "12",
pages = "1165--1172",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression domain of the Myc antagonist Mxi1

AU - Rao, Govinda

AU - Alland, Leila

AU - Guida, Peter

AU - Schreiber-Agus, Nicole

AU - Chen, Ken

AU - Chin, Lynda

AU - Rochelle, Julie M.

AU - Seldin, Michael F

AU - Skoultchi, Arthur I.

AU - DePinho, Ronald A.

PY - 1996

Y1 - 1996

N2 - Mxi1 is a basic region helix-loop-helix leucine zipper (bHLH/LZ) protein that, in association with Max, antagonizes Myc oncogenic activities. A possible mechanistic basis for Mxi1-mediated repression was provided by the recent demonstration that the repressive potential of Mxi1 correlates with its ability to physically associate with mSin3B, one of two mammalian homologues of the yeast transcriptional repressor SIN3. Here, we sought to characterize more fully the physical properties of the second homologue, mSin3A and to determine whether the recruitment of mSin3A by Mxi1 is indeed required for anti-Myc activity. Transient transfection of mammalian cells showed that the mSin3A protein can associate with the strong repressive isoform of Mxi1 (Mxi1-SR) and that, like other Myc superfamily members, both mSin3A and Mxi1-SR localize to the nucleus. From a developmental standpoint, a comparative analysis of Myc, Mxi1-SR and Sin3A expression during postnatal mouse development and in differentiating mouse erythroleukemia (MEL) cells revealed that dramatic and reciprocal changes in Myc and Mxi1-SR mRNA levels are accompanied by minimal stage-specific changes in mSin3A gene expression. This constant expression profile, coupled with the observation that over-expression of mSin3A does not augment the anti-Myc activity of Mxi1-SR in the rat embryo fibroblast (REF) transformation assay, suggests that mSin3A is not a limiting factor in the regulation of Myc superfamily function. Finally, a mSin3A-Mxi1 fusion protein, in which the amino terminal mSin3-interacting domain of Mxi1-SR was replaced with the full-length mSin3A, exhibited a level of repression activity equivalent to, or greater than, the level of repression obtained with Mxi1-SR. Taken together, these observations directly demonstrate that the amino-terminal repression domain of Mxi1-SR functions solely to recruit mSin3A and possibly other proteins like mSin3A and this association is necessary for the anti-Myc activity of Mxi1-SR.

AB - Mxi1 is a basic region helix-loop-helix leucine zipper (bHLH/LZ) protein that, in association with Max, antagonizes Myc oncogenic activities. A possible mechanistic basis for Mxi1-mediated repression was provided by the recent demonstration that the repressive potential of Mxi1 correlates with its ability to physically associate with mSin3B, one of two mammalian homologues of the yeast transcriptional repressor SIN3. Here, we sought to characterize more fully the physical properties of the second homologue, mSin3A and to determine whether the recruitment of mSin3A by Mxi1 is indeed required for anti-Myc activity. Transient transfection of mammalian cells showed that the mSin3A protein can associate with the strong repressive isoform of Mxi1 (Mxi1-SR) and that, like other Myc superfamily members, both mSin3A and Mxi1-SR localize to the nucleus. From a developmental standpoint, a comparative analysis of Myc, Mxi1-SR and Sin3A expression during postnatal mouse development and in differentiating mouse erythroleukemia (MEL) cells revealed that dramatic and reciprocal changes in Myc and Mxi1-SR mRNA levels are accompanied by minimal stage-specific changes in mSin3A gene expression. This constant expression profile, coupled with the observation that over-expression of mSin3A does not augment the anti-Myc activity of Mxi1-SR in the rat embryo fibroblast (REF) transformation assay, suggests that mSin3A is not a limiting factor in the regulation of Myc superfamily function. Finally, a mSin3A-Mxi1 fusion protein, in which the amino terminal mSin3-interacting domain of Mxi1-SR was replaced with the full-length mSin3A, exhibited a level of repression activity equivalent to, or greater than, the level of repression obtained with Mxi1-SR. Taken together, these observations directly demonstrate that the amino-terminal repression domain of Mxi1-SR functions solely to recruit mSin3A and possibly other proteins like mSin3A and this association is necessary for the anti-Myc activity of Mxi1-SR.

KW - Cotransformation

KW - mSin3A

KW - Mxi1

KW - Myc

KW - PAH domain

KW - Repression

UR - http://www.scopus.com/inward/record.url?scp=9244234957&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=9244234957&partnerID=8YFLogxK

M3 - Article

C2 - 8649810

AN - SCOPUS:9244234957

VL - 12

SP - 1165

EP - 1172

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 5

ER -