Metastasis-Suppressor Genes: a Review and Perspective on an Emerging Field

Yoshida, Barbara A.; Sokoloff, Mitchell; Welch, Danny R.; Rinker‐Schaeffer, Carrie W.

doi:10.1093/jnci/92.21.1717

Cited by 226 publications

(126 citation statements)

References 101 publications

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“…The following oligonucleotides were used to generate serine to alanine mutants: serine 297 to alanine (KSR 297S-A ), 5Ј-TCA CAC GGA GCA AGG CCC ACG AGT CCC AGC-3Ј; serine 392 1 The abbreviations used are: MAPK, mitogen-activated protein kinase; pMAPK, phosphorylated mitogen-activated protein kinase; KSR, kinase suppressor of Ras; HPLC, high performance liquid chromatography; rNm23-H1, recombinant Nm23-H1. …”

Section: Site-directed Mutation Of Ksrmentioning

confidence: 99%

“…1). The nm23 gene family was described by its reduced expression in highly metastatic murine melanoma cell lines, as compared with related, tumorigenic but less metastatic cell lines (2) and consists of eight family members (reviewed in Ref.…”

mentioning

confidence: 99%

“…Whereas many of the Arabidopsis "two-component" proteins were hybrids, a single protein containing both the sensor histidine protein kinase and aspartate regulator domains, the Arabidopsis ERS histidine sensor kinase was found by twohybrid analysis to interact with the N-terminal portion of CTR1 (78). CTR1 was not reported to be a typical aspartatephosphorylated response protein, but led to a diminution of the mitogen-activated protein kinase (MAPK) 1 pathway by an unknown mechanism and thus represented a novel suppressive pathway extending from the two-component system. Whereas it was originally reported to be homologous to mammalian Raf family members (78,79), we report herein that CTR1 also shares significant homology to the kinase suppressor of Ras (KSR) (80), a putative scaffold protein for the MAPK pathway (reviewed in Ref.…”

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Nm23-H1 Metastasis Suppressor Phosphorylation of Kinase Suppressor of Ras via a Histidine Protein Kinase Pathway

Hartsough¹,

Morrison²,

Salerno³

et al. 2002

Journal of Biological Chemistry

181

151

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The metastasis-suppressive activity of Nm23-H1 was previously correlated with its in vitro histidine protein kinase activity, but physiological substrates have not been identified. We hypothesized that proteins that interact with histidine kinases throughout evolution may represent partners for Nm23-H1 and focused on the interaction of Arabidopsis "two-component" histidine kinase ERS with CTR1. A mammalian homolog of CTR1 was previously reported to be c-Raf; we now report that CTR1 also exhibits homology to the kinase suppressor of Ras (KSR), a scaffold protein for the mitogen-activated protein kinase (MAPK) cascade. Nm23-H1 co-immunoprecipitated KSR from lysates of transiently transfected 293T cells and at endogenous protein expression levels in MDA-MB-435 breast carcinoma cells. Autophosphorylated recombinant Nm23-H1 phosphorylated KSR in vitro. Phosphoamino acid analysis identified serine as the major target, and two peaks of Nm23-H1 phosphorylation were identified upon high performance liquid chromatography analysis of KSR tryptic peptides. Using site-directed mutagenesis, we found that Nm23-H1 phosphorylated KSR serine 392, a 14-3-3-binding site, as well as serine 434 when serine 392 was mutated. Phosphorylated MAPK but not total MAPK levels were reduced in an nm23-H1 transfectant of MDA-MB-435 cells. The data identify a complex in vitro histidine-to-serine protein kinase pathway, which may contribute to signal transduction and metastasis.Metastasis suppressor genes are credentialed by their ability to suppress metastatic potential in vivo upon injection of a transfected tumor cell line, without a concomitant reduction in primary tumor size (reviewed in Ref. 1). The nm23 gene family was described by its reduced expression in highly metastatic murine melanoma cell lines, as compared with related, tumorigenic but less metastatic cell lines (2) and consists of eight family members (reviewed in Ref.3). In a recent review, 18 of 24 studies found a significant relationship between decreased Nm23 expression in primary human breast carcinomas and an aspect of aggressive clinical course (patient survival, lymph node metastasis, etc.), although Nm23 expression does not represent an independent prognostic or predictive factor (4). Ten transfection experiments have shown that nm23-transfected, metastatically competent cell lines are 40 -98% less metastatic in vivo than control transfectants (5-14). For nm23-H1, the most studied member, overexpression in human MDA-MB-435 breast carcinoma cells reduced colonization in soft agar, both unstimulated and transforming growth factor-␤-stimulated (6), and invasion/motility to a variety of chemoattractants (15-17). Nm23-H1 breast carcinoma transfectants exhibited morphological (ascinus formation) and biosynthetic aspects of differentiation in three-dimensional culture (18), and this finding is supported by similar studies in neural cells (19 -25).Despite extensive work, the biochemical mechanism of action whereby Nm23-H1 suppresses the metastatic potential of cancer cells is unk...

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Section: Site-directed Mutation Of Ksrmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Nm23-H1 Metastasis Suppressor Phosphorylation of Kinase Suppressor of Ras via a Histidine Protein Kinase Pathway

Hartsough¹,

Morrison²,

Salerno³

et al. 2002

Journal of Biological Chemistry

181

151

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“…The APC gene might fall into this category, at least in part, because replacement of chromosome 5 into a colon cancer cell line, SW480, lacking the APC function, strongly suppresses tumorigenicity in nude mice (Goyette et al, 1992). The last group of genes does not affect tumor formation but inhibits metastasis in mice, indicating that the genes responsible for metastasis suppression are distinct from those responsible for tumor suppression in some cases (Yoshida et al, 2000). The KAI-1 gene was isolated by functional complementation for metastasis in a rat prostate cancer cell line (Dong et al, 1995).…”

Section: Malignant Phenotypes Suppressed By Genetic Complementationmentioning

confidence: 99%

Functional cloning of a tumor suppressor gene, TSLC1, in human non-small cell lung cancer

Murakami¹

2002

Oncogene

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“…In addition to metastasis-promoting genes, a new class of molecules called metastasis suppressors has been described (reviewed in Refs. [2][3][4][5]. By definition, metastasis suppressors inhibit metastasis without blocking primary tumor growth, presumably by inhibiting one or more steps necessary for metastasis.…”

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confidence: 99%

Breast Cancer Metastasis Suppressor 1 (BRMS1) Forms Complexes with Retinoblastoma-binding Protein 1 (RBP1) and the mSin3 Histone Deacetylase Complex and Represses Transcription

Meehan

Samant

Hopper

et al. 2004

Journal of Biological Chemistry

160

139

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Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis of multiple human and murine cancer cells without inhibiting tumorigenicity. By yeast two-hybrid and co-immunoprecipitation, BRMS1 interacts with retinoblastoma binding protein 1 and at least seven members of the mSin3 histone deacetylase (HDAC) complex in human breast and melanoma cell lines. BRMS1 co-immunoprecipitates enzymatically active HDAC proteins and represses transcription when recruited to a Gal4 promoter in vivo. BRMS1 exists in large mSin3 complex(es) of ϳ1.4 -1.9 MDa, but also forms smaller complexes with HDAC1. Deletion analyses show that the carboxyl-terminal 42 amino acids of BRMS1 are not critical for interaction with much of the mSin3 complex and that BRMS1 appears to have more than one binding point to the complex. These results further show that BRMS1 may participate in transcriptional regulation via interaction with the mSin3⅐HDAC complex and suggest a novel mechanism by which BRMS1 might suppress cancer metastasis.The complex process of cancer cell dissemination and the establishment of secondary foci involves the acquisition of multiple abilities by metastatic cells. For example, blood-borne metastasis requires cells to invade from the primary tumor, enter the circulation, survive transport, arrest at a secondary site, recruit a blood supply, and proliferate at that site (1). The ability to accomplish all of these steps likely involves changes in, and coordinated expression of, a large assortment of genes. Consistent with this notion, several genes, proteins, and pathways have been associated with metastatic progression, including oncogenes, motility factors, and matrix metalloproteinases (1, 2). In addition to metastasis-promoting genes, a new class of molecules called metastasis suppressors has been described (reviewed in Refs. 2-5). By definition, metastasis suppressors inhibit metastasis without blocking primary tumor growth, presumably by inhibiting one or more steps necessary for metastasis. To date, 13 metastasis suppressor genes have been identified that reduce the metastatic ability of cancer cell line(s) in vivo without affecting tumorigenicity, namely breast cancer metastasis suppressor 1 (BRMS1), 1 CRSP3, DRG1, KAI1, KISS1, MKK4, NM23, RhoGDI2, RKIP, SSeCKs, VDUP1, E-cadherin, and TIMPs (reviewed in Refs. 4 and 5).We identified BRMS1 using differential display to compare highly metastatic breast carcinoma cells with related but metastasis-suppressed cells (6). Enforced expression of BRMS1 suppressed metastasis in three animal models, namely human breast (6), murine mammary (7), and human melanoma cells (8). Additionally, BRMS1 mapped to loci in murine (7) and human (6) genomes that had previously been implicated in metastasis control (9). The BRMS1 protein localized to nuclei and restored gap junctional intercellular communication in both breast and melanoma tumor cell lines (8,10,11), but its molecular functions remain to be elucidated.One approach to determine a mechanism of action involves identifying which...

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Metastasis-Suppressor Genes: a Review and Perspective on an Emerging Field

Cited by 226 publications

References 101 publications

Nm23-H1 Metastasis Suppressor Phosphorylation of Kinase Suppressor of Ras via a Histidine Protein Kinase Pathway

Nm23-H1 Metastasis Suppressor Phosphorylation of Kinase Suppressor of Ras via a Histidine Protein Kinase Pathway

Functional cloning of a tumor suppressor gene, TSLC1, in human non-small cell lung cancer

Breast Cancer Metastasis Suppressor 1 (BRMS1) Forms Complexes with Retinoblastoma-binding Protein 1 (RBP1) and the mSin3 Histone Deacetylase Complex and Represses Transcription

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