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 Popova, Dieter Brömme, Theresa H.T. Coetzer, Stephen P. Bottomley, Iaroslava A. Boulynko, Sergei Grigoryev, James C. Whisstock

Research output: Contribution to journalArticle

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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 (US)
Pages (from-to)13192-13201
Number of pages10
JournalJournal of Biological Chemistry
Volume277
Issue number15
DOIs
StatePublished - Apr 12 2002

Fingerprint

Serpins
Papain
Cysteine Proteases
Heterochromatin
Cell proliferation
Chromatin
Cell Proliferation
Condensation
AT-Hook Motifs
Cells
Cathepsin L
Nuclear Localization Signals
Retinoblastoma Protein
Cell Nucleus Active Transport
Hooks
Sequence Deletion
Nuclear Proteins
Blood Cells
Catalytic Domain
Blood

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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

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

Research output: Contribution to journalArticle

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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.

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AU - Whisstock, James C.

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