A requirement for dimerization of HP1Hsalpha in suppression of breast cancer invasion

Laura E Norwood; Timothy J Moss; Naira V Margaryan; Sara L Cook; Lindsay Wright; Elisabeth A Seftor; Mary J C Hendrix; Dawn A Kirschmann; Lori L Wallrath

doi:10.1074/jbc.M512454200

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A requirement for dimerization of HP1Hsalpha in suppression of breast cancer invasion

Journal article

Open access

Peer reviewed

A requirement for dimerization of HP1Hsalpha in suppression of breast cancer invasion

Laura E Norwood, Timothy J Moss, Naira V Margaryan, Sara L Cook, Lindsay Wright, Elisabeth A Seftor, Mary J C Hendrix, Dawn A Kirschmann and Lori L Wallrath

The Journal of biological chemistry, Vol.281(27), pp.18668-18676

07/07/2006

DOI: 10.1074/jbc.M512454200

PMID: 16648629

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Abstract

The development and progression of cancer is controlled by gene expression, often regulated through chromatin packaging. Heterochromatin protein 1(Hsalpha) (HP1(Hsalpha)), one of three human HP1 family members, participates in heterochromatin formation and gene regulation. HP1(Hsalpha) possesses an amino-terminal chromodomain, which binds methylated lysine 9 of histone H3 (meK9 H3), and a carboxyl-terminal chromoshadow domain (CSD) that is required for dimerization and interaction with partner proteins. HP1(Hsalpha) is down-regulated in invasive metastatic breast cancer cells compared with poorly invasive nonmetastatic breast cancer cells. Expression of EGFP-HP1(Hsalpha) in highly invasive MDA-MB-231 cells causes a reduction in in vitro invasion, without affecting cell growth. Conversely, knock-down of HP1(Hsalpha) levels in the poorly invasive breast cancer cell line MCF-7 increased invasion, without affecting cell growth. To determine whether functions of the CSD were required for the regulation of invasion, mutant forms of HP1(Hsalpha) were expressed in MDA-MB-231 cells. A W174A mutation that disrupts interactions between HP1(Hsalpha) and PXVXL-containing partner proteins reduced invasion similar to that of the wild type protein. In contrast, an I165E mutation that disrupts dimerization of HP1(Hsalpha) did not decrease invasion. No gross changes in localization and abundance of HP1(Hsbeta), HP1(Hsgamma), and meK9 H3 were observed upon expression of wild type and mutant forms of HP1(Hsalpha) in MDA-MB-231 cells. Taken together, these data demonstrate that modulation of HP1(Hsalpha) alters the invasive potential of breast cancer cells through mechanisms requiring HP1 dimerization, but not interactions with PXVXL-containing proteins.

Protein Structure, Tertiary

Breast Neoplasms - genetics

Breast Neoplasms - pathology

Humans

Gene Expression Regulation, Neoplastic

Cell Line, Tumor

Female

Structure-Activity Relationship

Neoplasm Invasiveness - genetics

Dimerization

Chromosomal Proteins, Non-Histone - chemistry

Chromosomal Proteins, Non-Histone - genetics

Details

Title: Subtitle: A requirement for dimerization of HP1Hsalpha in suppression of breast cancer invasion
Creators: Laura E Norwood - Department of Biochemistry, University of Iowa, Iowa City, Iowa 52242, USA
Timothy J Moss
Naira V Margaryan
Sara L Cook
Lindsay Wright
Elisabeth A Seftor
Mary J C Hendrix
Dawn A Kirschmann
Lori L Wallrath
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.281(27), pp.18668-18676
DOI: 10.1074/jbc.M512454200
PMID: 16648629
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: T32 GM007337 / NIGMS NIH HHS
Language: English
Date published: 07/07/2006
Academic Unit: Biochemistry and Molecular Biology
Record Identifier: 9984025278102771

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