RESUMO
Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (â¼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.
Assuntos
Proteína BRCA1/genética , Cistadenocarcinoma Seroso/prevenção & controle , Mifepristona/farmacologia , Neoplasias Ovarianas/prevenção & controle , Progesterona/antagonistas & inibidores , Adulto , Animais , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/prevenção & controle , Cistadenocarcinoma Seroso/química , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Modelos Animais de Doenças , Estradiol/administração & dosagem , Feminino , Humanos , Camundongos , Pessoa de Meia-Idade , Mifepristona/uso terapêutico , Mutação , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Experimentais/prevenção & controle , Neoplasias Ovarianas/induzido quimicamente , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ovário/patologia , Ovário/cirurgia , Progesterona/administração & dosagem , Progesterona/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Salpingo-Ooforectomia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.
Assuntos
Antineoplásicos/farmacologia , Cistadenocarcinoma Seroso/genética , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/genética , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Instabilidade Cromossômica , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/secundário , RNA Helicases DEAD-box/genética , Reparo do DNA , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Estudos de Viabilidade , Feminino , Humanos , Camundongos , Camundongos Knockout , Mutação , Gradação de Tumores , Metástase Neoplásica/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , PTEN Fosfo-Hidrolase/genética , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Cultura Primária de Células , Ribonuclease III/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
The anaphase promoting complex (APC) or cyclosome is a multisubunit E3 ubiquitin ligase. Cdc20 (fizzy (fzy)) or p55CDC, and Cdh1 (Hct1, srw1 or fizzy-related 1 (fzr1)) encode two adaptor proteins that bring substrates to the APC. Both APC-Cdc20 and APC-Cdh1 have been implicated in the control of mitosis through mediating ubiquitination of mitotic regulators, such as cyclin B1 and securin. However, the importance of Cdh1 function in vivo and whether its function is redundant with that of Cdc20 are unclear. Here we have analysed mice lacking Cdh1. We show that Cdh1 is essential for placental development and that its deficiency causes early lethality. Cdhl-deficient mouse embryonic fibroblasts (MEFs) entered replicative senescence prematurely because of stabilization of Ets2 and subsequent activation of p6(Ink4a) expression. These results have uncovered an unexpected role of the APC in maintaining replicative lifespan of MEFs. Further, Cdh1 heterozygous mice show defects in late-phase long-term potentiation (L-LTP) in the hippocampus and are deficient in contextual fear-conditioning, suggesting that Cdh1 has a role in learning and memory.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Senescência Celular , Memória/fisiologia , Complexos Ubiquitina-Proteína Ligase/metabolismo , Ciclossomo-Complexo Promotor de Anáfase , Animais , Proteínas Cdh1 , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Perda do Embrião/metabolismo , Fibroblastos/enzimologia , Fibroblastos/patologia , Heterozigoto , Técnicas In Vitro , Camundongos , Estabilidade Proteica , Proteína Proto-Oncogênica c-ets-2/metabolismo , Especificidade por SubstratoRESUMO
Oocytes in embryonic ovaries enter meiosis I and arrest in the diplonema stage. Perturbations in meiosis I, such as abnormal double-strand break (DSB) formation and repair, adversely affect oocyte survival. We previously discovered that HORMAD1 is a critical component of the synaptonemal complex but not essential for oocyte survival. No significant differences were observed in the number of primordial, primary, secondary, and developing follicles between wild-type and Hormad1(−/−)newborn, 8-day, and 80-day ovaries. Meiosis I progression in Hormad1(−/−) embryonic ovaries was normal through the zygotene stage and in oocytes arrested in diplonema; however, we did not visualize oocytes with completely synapsed chromosomes. We investigated effects of HORMAD1 deficiency on the kinetics of DNA DSB formation and repair in the mouse ovary. We irradiated Embryonic Day 16.5 wild-type and Hormad1(−/−) ovaries and monitored DSB repair using gammaH2AX, RAD51, and DMC1 immunofluorescence. Our results showed a significant drop in unrepaired DSBs in the irradiated Hormad1(−/−) zygotene oocytes as compared to the wild-type oocytes. Moreover, Hormad1 deficiency rescued Dmc1(−/−) oocytes. These results indicate that Hormad1 deficiency promotes DMC1-independent DSB repairs, which in turn helps asynaptic Hormad1(−/−) oocytes resist perinatal loss.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Meiose/genética , Animais , Pontos de Checagem do Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Feminino , Camundongos , Camundongos Knockout , Oócitos/metabolismoRESUMO
Meiosis is unique to germ cells and essential for reproduction. During the first meiotic division, homologous chromosomes pair, recombine, and form chiasmata. The homologues connect via axial elements and numerous transverse filaments to form the synaptonemal complex. The synaptonemal complex is a critical component for chromosome pairing, segregation, and recombination. We previously identified a novel germ cell-specific HORMA domain encoding gene, Hormad1, a member of the synaptonemal complex and a mammalian counterpart to the yeast meiotic HORMA domain protein Hop1. Hormad1 is essential for mammalian gametogenesis as knockout male and female mice are infertile. Hormad1 deficient (Hormad1(-/) (-)) testes exhibit meiotic arrest in the early pachytene stage, and synaptonemal complexes cannot be visualized by electron microscopy. Hormad1 deficiency does not affect localization of other synaptonemal complex proteins, SYCP2 and SYCP3, but disrupts homologous chromosome pairing. Double stranded break formation and early recombination events are disrupted in Hormad1(-/) (-) testes and ovaries as shown by the drastic decrease in the γH2AX, DMC1, RAD51, and RPA foci. HORMAD1 co-localizes with γH2AX to the sex body during pachytene. BRCA1, ATR, and γH2AX co-localize to the sex body and participate in meiotic sex chromosome inactivation and transcriptional silencing. Hormad1 deficiency abolishes γH2AX, ATR, and BRCA1 localization to the sex chromosomes and causes transcriptional de-repression on the X chromosome. Unlike testes, Hormad1(-/) (-) ovaries have seemingly normal ovarian folliculogenesis after puberty. However, embryos generated from Hormad1(-/) (-) oocytes are hyper- and hypodiploid at the 2 cell and 8 cell stage, and they arrest at the blastocyst stage. HORMAD1 is therefore a critical component of the synaptonemal complex that affects synapsis, recombination, and meiotic sex chromosome inactivation and transcriptional silencing.
Assuntos
Proteínas de Ciclo Celular/genética , Segregação de Cromossomos/genética , Meiose/genética , Mutação/genética , Recombinação Genética/genética , Complexo Sinaptonêmico/metabolismo , Aneuploidia , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Desenvolvimento Embrionário/genética , Feminino , Feto/citologia , Feto/metabolismo , Masculino , Camundongos , Proteínas Nucleares/metabolismo , Oócitos/citologia , Oócitos/metabolismo , Especificidade de Órgãos/genética , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Cromossomos Sexuais/genética , Espermatogênese/genética , Espermatozoides/citologia , Espermatozoides/metabolismo , Espermatozoides/ultraestrutura , Complexo Sinaptonêmico/ultraestrutura , Proteínas Supressoras de Tumor/metabolismoRESUMO
Expression of CCL23 is induced by external stimuli including PMA in monocytes, but its transcriptional regulation has not been studied to date. Serial deletion analysis of its 5' flanking region revealed that the region -293 to +31 was important for induction by PMA. Cis-acting elements at the -269/-264 (NFAT site), -167/-159 (NF-kappaB site), and -51/-43 (AP-1 site) positions were identified as the critical sites for the CCL23 expression in U937 cells. We demonstrated the binding of the transcription factors to the consensus sites. Specific inhibitors for signal pathways reduced PMA-induced expression of CCL23, confirming involvement of these transcription factors.
Assuntos
Quimiocinas CC/genética , Regulação da Expressão Gênica , Monócitos/fisiologia , Regiões Promotoras Genéticas/genética , Sequência de Bases , Sítios de Ligação , Carcinógenos/farmacologia , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Quimiocinas CC/metabolismo , Humanos , Dados de Sequência Molecular , Monócitos/citologia , Monócitos/efeitos dos fármacos , NF-kappa B/genética , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Ligação Proteica , Sequências Reguladoras de Ácido Nucleico , Acetato de Tetradecanoilforbol/farmacologia , Fator de Transcrição AP-1/metabolismo , Transcrição Gênica , Células U937RESUMO
In this paper, we investigate the optimal consumption and portfolio selection problem with negative wealth constraints for an economic agent who has a quadratic utility function of consumption and receives a constant labor income. Due to the property of the quadratic utility function, we separate our problem into two cases and derive the closed-form solutions for each case. We also illustrate some numerical implications of the optimal consumption and portfolio.
RESUMO
Following migration of primordial germ cells to the genital ridge, oogonia undergo several rounds of mitotic division and enter meiosis at approximately E13.5. Most oocytes arrest in the dictyate (diplotene) stage of meiosis circa E18.5. The genes necessary to drive oocyte differentiation in parallel with meiosis are unknown. Here, we have investigated whether expression of spermatogenesis and oogenesis bHLH transcription factor 1 (Sohlh1) and Sohlh2 coordinates oocyte differentiation within the embryonic ovary. We found that SOHLH2 protein was expressed in the mouse germline as early as E12.5 and preceded SOHLH1 protein expression, which occurred circa E15.5. SOHLH1 protein appearance at E15.5 correlated with SOHLH2 translocation from the cytoplasm into the nucleus and was dependent on SOHLH1 expression. NOBOX oogenesis homeobox (NOBOX) and LIM homeobox protein 8 (LHX8), two important regulators of postnatal oogenesis, were coexpressed with SOHLH1. Single deficiency of Sohlh1 or Sohlh2 disrupted the expression of LHX8 and NOBOX in the embryonic gonad without affecting meiosis. Sohlh1-KO infertility was rescued by conditional expression of the Sohlh1 transgene after the onset of meiosis. However, Sohlh1 or Sohlh2 transgene expression could not rescue Sohlh2-KO infertility due to a lack of Sohlh1 or Sohlh2 expression in rescued mice. Our results indicate that Sohlh1 and Sohlh2 are essential regulators of oocyte differentiation but do not affect meiosis I.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Meiose , Oócitos/fisiologia , Transporte Ativo do Núcleo Celular , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Desenvolvimento Embrionário , Feminino , Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Masculino , Camundongos Transgênicos , Regiões Promotoras Genéticas , Caracteres Sexuais , Fatores de Transcrição/metabolismo , Ativação TranscricionalRESUMO
CCL15 exerts biological effects on a variety of cells, including monocytes. NF-kappaB has been reported to be involved in the transcription of the CCL15 gene. In this study, we have identified an AP-1 element located at -76/-65, which appears to regulate the transcription of the CCL15 gene. We also confirmed that the AP-1 factor binds to the element. Specific inhibitors for MAPK pathways and expression of dominant negative MKK4 or JNK1 reduced PMA-induced transcriptional activation of CCL15. Our findings indicate that transcription of the CCL15 gene is regulated by AP-1 and NF-kappaB through MEK and JNK MAPK pathways in monocytoid cells.
Assuntos
Quimiocinas CC/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Monócitos/metabolismo , Monocinas/genética , NF-kappa B/metabolismo , Elementos de Resposta/genética , Fator de Transcrição AP-1/metabolismo , Transcrição Gênica/efeitos dos fármacos , Humanos , Proteínas Inflamatórias de Macrófagos , Monócitos/efeitos dos fármacos , Mutação Puntual/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Ligação Proteica , Transdução de Sinais/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia , Células U937RESUMO
Mannasantin B, a dilignan structurally related to manssantin A, is an inhibitor of NF-kappaB transactivation. In the present study, we found that it inhibited PMA-induced expression of IL-1beta, IL-1beta mRNA, and IL-1beta promoter activity in U937 cells with IC50 values of about 50 nM. It also inhibited NF-IL6- and NF-kappaB-induced activation of IL-1beta, with IC50 values of 78 nM and 1.6 microM, respectively, revealing a potent inhibitory effect on NF-IL6. Electrophoretic mobility shift assays showed that manassantin B had an inhibitory effect on DNA binding by NF-IL6, but not by NF-kappaB. Further analysis revealed that transactivation by NF-IL6 was also inhibited. Our results indicate that manassantin B suppresses expression of IL-1beta in promonocytic cells by inhibiting not only NF-kappaB but also NF-IL6 activity. Furthermore, our observations suggest that manassantin B may be clinically useful as a potent inhibitor of NF-IL6 activity.
Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Furanos/farmacologia , Saururaceae/metabolismo , Acetato de Tetradecanoilforbol/antagonistas & inibidores , Relação Dose-Resposta a Droga , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Concentração Inibidora 50 , Interleucina-1/genética , Interleucina-1/metabolismo , Saururaceae/genética , Saururaceae/imunologia , Ativação Transcricional/efeitos dos fármacos , Transfecção , Células U937RESUMO
Uterine leiomyomas are benign tumors that can cause pain, bleeding, and infertility in some women. Mediator complex subunit 12 (MED12) exon 2 variants are associated with uterine leiomyomas; however, the causality of MED12 variants, their genetic mode of action, and their role in genomic instability have not been established. Here, we generated a mouse model that conditionally expresses a Med12 missense variant (c.131G>A) in the uterus and demonstrated that this alteration alone promotes uterine leiomyoma formation and hyperplasia in both WT mice and animals harboring a uterine mesenchymal cell-specific Med12 deletion. Compared with WT animals, expression of Med12 c.131G>A in conditional Med12-KO mice resulted in earlier onset of leiomyoma lesions that were also greater in size. Moreover, leiomyomatous, Med12 c.131G>A variant-expressing uteri developed chromosomal rearrangements. Together, our results show that the common human leiomyoma-associated MED12 variant can cause leiomyomas in mice via a gain of function that drives genomic instability, which is frequently observed in human leiomyomas.
Assuntos
Instabilidade Genômica , Leiomioma/metabolismo , Complexo Mediador/metabolismo , Mutação de Sentido Incorreto , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/metabolismo , Substituição de Aminoácidos , Animais , Aberrações Cromossômicas , Feminino , Humanos , Leiomioma/genética , Leiomioma/patologia , Complexo Mediador/genética , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologiaRESUMO
Leukotactin-1 (Lkn-1)/CCL15, is a recently cloned chemotactic chemokine that appears to play important roles in the inflammatory process by recruiting immune cells to inflammatory sites. Expression of the Lkn-1/CCL15 gene is inducible in monocytes but its transcriptional regulation has not been studied. To identify Lkn-1/CCL15 regulatory sequences in monocytic cells, U937 cells were transiently transfected with the luciferase reporter gene linked to various deletions of the Lkn-1/CCL15 promoter region. The region -269 to -43 bp from the transcription start site proved to be important for induction by PMA. This region contained two potential NF-kappaB sites: one between -191 and -182 bp, and the other between -60 and -51 bp. Mutation of either element reduced PMA-induced expression and electrophoretic mobility shift assays revealed that NF-kappaB recognized both potential NF-kappaB sites. In addition, PMA-induction of Lkn-1/CCL15 in transiently transfected U937 cells was blocked by proteasome inhibitor 1. These observations demonstrate that the two NF-kappaB binding sites are essential for PMA-induced Lkn-1/CCL15 expression in human monocytes.
Assuntos
Quimiocinas CC/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Monócitos/efeitos dos fármacos , NF-kappa B/metabolismo , Sequências Reguladoras de Ácido Nucleico , Acetato de Tetradecanoilforbol/farmacologia , Sítios de Ligação , Linhagem Celular , Quimiocinas CC/metabolismo , Inibidores Enzimáticos/metabolismo , Humanos , Monócitos/citologia , Monócitos/fisiologiaRESUMO
The present study was undertaken to determine the expression and biological significance of HORMAD1 in human epithelial ovarian carcinoma. We found that a substantial proportion of human epithelial ovarian cancers expressed HORMAD1. In vitro, HORMAD1 siRNA enhanced docetaxel induced apoptosis and substantially reduced the invasive and migratory potential of ovarian cancer cells (2774). In vivo, HORMAD1 siRNA-DOPC treatment resulted in reduced tumor weight, which was further enhanced in combination with cisplatin. HORMAD1 gene silencing resulted in significantly reduced VEGF protein levels and microvessel density compared to controls. Our data suggest that HORMAD1 may be an important therapeutic target.
Assuntos
Proteínas de Ciclo Celular/fisiologia , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Animais , Carcinoma Epitelial do Ovário , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Invasividade Neoplásica , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , RNA Mensageiro/análise , RNA Interferente Pequeno/genética , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
FTO (fat mass and obesity associated) was identified as an obesity-susceptibility gene by several independent large-scale genome association studies. A cluster of SNPs (single nucleotide polymorphism) located in the first intron of FTO was found to be significantly associated with obesity-related traits, such as body mass index, hip circumference, and body weight. FTO encodes a protein with a novel C-terminal α-helical domain and an N-terminal double-strand ß-helix domain which is conserved in Fe(II) and 2-oxoglutarate-dependent oxygenase family. In vitro, FTO protein can demethylate single-stranded DNA or RNA with a preference for 3-methylthymine or 3-methyluracil. Its physiological substrates and function, however, remain to be defined. Here we report the generation and analysis of mice carrying a conditional deletion allele of Fto. Our results demonstrate that Fto plays an essential role in postnatal growth. The mice lacking Fto completely display immediate postnatal growth retardation with shorter body length, lower body weight, and lower bone mineral density than control mice, but their body compositions are relatively normal. Consistent with the growth retardation, the Fto mutant mice have reduced serum levels of IGF-1. Moreover, despite the ubiquitous expression of Fto, its specific deletion in the nervous system results in similar phenotypes as the whole body deletion, indicating that Fto functions in the central nerve system to regulate postnatal growth.
Assuntos
Peso Corporal/genética , Encéfalo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Animais , Western Blotting , Peso Corporal/fisiologia , Densidade Óssea/fisiologia , Encéfalo/crescimento & desenvolvimento , Gorduras na Dieta/administração & dosagem , Feminino , Predisposição Genética para Doença , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/genética , Obesidade/fisiopatologia , Proteínas/metabolismo , Proteínas/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Multiple CC chemokines bind to CCR1, which plays important roles in immune and inflammatory responses. To search for proteins involved in the CCR1 signaling pathway, we screened a yeast two-hybrid library using the cytoplasmic tail of CCR1 as the bait. One of the positive clones contained an open reading frame of 456bp, of which the nucleotide sequence was identical to that of proteolipid protein 2 (PLP2), also known as protein A4. Mammalian two-hybrid and coimmunoprecipitation analyses demonstrated the association of PLP2/A4 with CCR1. Indirect immunofluorescence analysis revealed that PLP2/A4 was predominantly located in plasma membrane and colocalized with CCR1 in transfected human HEK293 cells. In addition, focal staining of CCR1 appeared on the periphery of the membrane upon short exposure to Leukotactin-1(Lkn-1)/CCL15, a CCR1 agonist, and was costained with PLP2/A4 on the focal regions. PLP2/A4 mRNAs were detected in various cells such as U-937, HL-60, HEK293, and HOS cells. Overexpression of PLP2/A4 stimulated a twofold increase in the agonist-induced migration of HOS/CCR1 cells, implicating a functional role for PLP2/A4 in the chemotactic processes via CCR1.