Inhibitory activity of a heterochromatin-associated serpin (MENT) against papain-like cysteine proteinases affects chromatin structure and blocks cell proliferation

James A. Irving, Sain S. Shushanov, Robert N. Pike, Evgenya Y. Popova, Dieter Brömme, Theresa H.T. Coetzer, Stephen P. Bottomley, Iaroslava A. Boulynko, Sergei A. Grigoryev, James C. Whisstock

Research output: Contribution to journalArticleResearchpeer-review

79 Citations (Scopus)

Abstract

MENT (Myeloid and Erythroid Nuclear Termination stage-specific protein) is a developmentally regulated chromosomal serpin that condenses chromatin in terminally differentiated avian blood cells. We show that MENT is an effective inhibitor of the papain-like cysteine proteinases cathepsins L and V. In addition, ectopic expression of MENT in mammalian cells is apparently sufficient to inhibit a nuclear papain-like cysteine proteinase and prevent degradation of the retinoblastoma protein, a major regulator of cell proliferation. MENT also accumulates in the nucleus, causes a strong block in proliferation, and promotes condensation of chromatin. Variants of MENT with mutations or deletions within the M-loop, which contains a nuclear localization signal and an AT-hook motif, reveal that this region mediates nuclear transport and morphological changes associated with chromatin condensation. Non-inhibitory mutants of MENT were constructed to determine whether its inhibitory activity has a role in blocking proliferation. These mutations changed the mode of association with chromatin and relieved the block in proliferation, without preventing transport to the nucleus. We conclude that the repressive effect of MENT on chromatin is mediated by its direct interaction with a nuclear protein that has a papain-like cysteine proteinase active site.

Original languageEnglish
Pages (from-to)13192-13201
Number of pages10
JournalJournal of Biological Chemistry
Volume277
Issue number15
DOIs
Publication statusPublished - 12 Apr 2002

Cite this

Irving, James A. ; Shushanov, Sain S. ; Pike, Robert N. ; Popova, Evgenya Y. ; Brömme, Dieter ; Coetzer, Theresa H.T. ; Bottomley, Stephen P. ; Boulynko, Iaroslava A. ; Grigoryev, Sergei A. ; Whisstock, James C. / Inhibitory activity of a heterochromatin-associated serpin (MENT) against papain-like cysteine proteinases affects chromatin structure and blocks cell proliferation. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 15. pp. 13192-13201.
@article{fcfacd402cbb4c7fb3e5b2cbf3554fdf,
title = "Inhibitory activity of a heterochromatin-associated serpin (MENT) against papain-like cysteine proteinases affects chromatin structure and blocks cell proliferation",
abstract = "MENT (Myeloid and Erythroid Nuclear Termination stage-specific protein) is a developmentally regulated chromosomal serpin that condenses chromatin in terminally differentiated avian blood cells. We show that MENT is an effective inhibitor of the papain-like cysteine proteinases cathepsins L and V. In addition, ectopic expression of MENT in mammalian cells is apparently sufficient to inhibit a nuclear papain-like cysteine proteinase and prevent degradation of the retinoblastoma protein, a major regulator of cell proliferation. MENT also accumulates in the nucleus, causes a strong block in proliferation, and promotes condensation of chromatin. Variants of MENT with mutations or deletions within the M-loop, which contains a nuclear localization signal and an AT-hook motif, reveal that this region mediates nuclear transport and morphological changes associated with chromatin condensation. Non-inhibitory mutants of MENT were constructed to determine whether its inhibitory activity has a role in blocking proliferation. These mutations changed the mode of association with chromatin and relieved the block in proliferation, without preventing transport to the nucleus. We conclude that the repressive effect of MENT on chromatin is mediated by its direct interaction with a nuclear protein that has a papain-like cysteine proteinase active site.",
author = "Irving, {James A.} and Shushanov, {Sain S.} and Pike, {Robert N.} and Popova, {Evgenya Y.} and Dieter Br{\"o}mme and Coetzer, {Theresa H.T.} and Bottomley, {Stephen P.} and Boulynko, {Iaroslava A.} and Grigoryev, {Sergei A.} and Whisstock, {James C.}",
year = "2002",
month = "4",
day = "12",
doi = "10.1074/jbc.M108460200",
language = "English",
volume = "277",
pages = "13192--13201",
journal = "Journal of Biological Chemistry",
issn = "1083-351X",
publisher = "American Society for Biochemistry and Molecular Biology",
number = "15",

}

Inhibitory activity of a heterochromatin-associated serpin (MENT) against papain-like cysteine proteinases affects chromatin structure and blocks cell proliferation. / Irving, James A.; Shushanov, Sain S.; Pike, Robert N.; Popova, Evgenya Y.; Brömme, Dieter; Coetzer, Theresa H.T.; Bottomley, Stephen P.; Boulynko, Iaroslava A.; Grigoryev, Sergei A.; Whisstock, James C.

In: Journal of Biological Chemistry, Vol. 277, No. 15, 12.04.2002, p. 13192-13201.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Inhibitory activity of a heterochromatin-associated serpin (MENT) against papain-like cysteine proteinases affects chromatin structure and blocks cell proliferation

AU - Irving, James A.

AU - Shushanov, Sain S.

AU - Pike, Robert N.

AU - Popova, Evgenya Y.

AU - Brömme, Dieter

AU - Coetzer, Theresa H.T.

AU - Bottomley, Stephen P.

AU - Boulynko, Iaroslava A.

AU - Grigoryev, Sergei A.

AU - Whisstock, James C.

PY - 2002/4/12

Y1 - 2002/4/12

N2 - MENT (Myeloid and Erythroid Nuclear Termination stage-specific protein) is a developmentally regulated chromosomal serpin that condenses chromatin in terminally differentiated avian blood cells. We show that MENT is an effective inhibitor of the papain-like cysteine proteinases cathepsins L and V. In addition, ectopic expression of MENT in mammalian cells is apparently sufficient to inhibit a nuclear papain-like cysteine proteinase and prevent degradation of the retinoblastoma protein, a major regulator of cell proliferation. MENT also accumulates in the nucleus, causes a strong block in proliferation, and promotes condensation of chromatin. Variants of MENT with mutations or deletions within the M-loop, which contains a nuclear localization signal and an AT-hook motif, reveal that this region mediates nuclear transport and morphological changes associated with chromatin condensation. Non-inhibitory mutants of MENT were constructed to determine whether its inhibitory activity has a role in blocking proliferation. These mutations changed the mode of association with chromatin and relieved the block in proliferation, without preventing transport to the nucleus. We conclude that the repressive effect of MENT on chromatin is mediated by its direct interaction with a nuclear protein that has a papain-like cysteine proteinase active site.

AB - MENT (Myeloid and Erythroid Nuclear Termination stage-specific protein) is a developmentally regulated chromosomal serpin that condenses chromatin in terminally differentiated avian blood cells. We show that MENT is an effective inhibitor of the papain-like cysteine proteinases cathepsins L and V. In addition, ectopic expression of MENT in mammalian cells is apparently sufficient to inhibit a nuclear papain-like cysteine proteinase and prevent degradation of the retinoblastoma protein, a major regulator of cell proliferation. MENT also accumulates in the nucleus, causes a strong block in proliferation, and promotes condensation of chromatin. Variants of MENT with mutations or deletions within the M-loop, which contains a nuclear localization signal and an AT-hook motif, reveal that this region mediates nuclear transport and morphological changes associated with chromatin condensation. Non-inhibitory mutants of MENT were constructed to determine whether its inhibitory activity has a role in blocking proliferation. These mutations changed the mode of association with chromatin and relieved the block in proliferation, without preventing transport to the nucleus. We conclude that the repressive effect of MENT on chromatin is mediated by its direct interaction with a nuclear protein that has a papain-like cysteine proteinase active site.

UR - http://www.scopus.com/inward/record.url?scp=0037066736&partnerID=8YFLogxK

U2 - 10.1074/jbc.M108460200

DO - 10.1074/jbc.M108460200

M3 - Article

VL - 277

SP - 13192

EP - 13201

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 15

ER -