PLU-1, a transcriptional repressor and putative testis-cancer antigen, has a specific expression and localisation pattern during meiosis

Madsen, Bo; Tarsounas, Madalena; Burchell, Joy; Hall, Debbie; Poulsom, Richard; Taylor‐Papadimitriou, Joyce

doi:10.1007/s00412-003-0252-6

Cited by 43 publications

(29 citation statements)

References 32 publications

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“…This result correlates with the high susceptibility of testes to cadmium-induced carcinogenesis (51,72,93), where the low MT level is thought to allow the elimination of cells with DNA damage rather than the mobilization of a repair response which could lead to defective progeny (93). Since the expression of PLU-1/JARID1B is very high in spermatogonia and in specific stages of meiosis (48), it is possible that the low expression of MTs in normal testes relates to the high expression of PLU-1/JARID1B. An inverse relationship between the expression of MTs and PLU-1/JARID1B is also seen in breast cancer cell lines.…”

Section: Discussionmentioning

confidence: 76%

“…Basal expression of MTs can be detected in the liver of rat, mouse, and human (where PLU-1/JARID1B expression is low [4]), and the proteins are induced severalfold following exposure to heavy metal ions, thus ensuring detoxification and protection from the carcinogenic effects of cadmium (26). In contrast, in rodent testes, where Plu-1/Jarid1B expression is high (48), basal levels of MTs are undetectable and are not induced by heavy metals. This result correlates with the high susceptibility of testes to cadmium-induced carcinogenesis (51,72,93), where the low MT level is thought to allow the elimination of cells with DNA damage rather than the mobilization of a repair response which could lead to defective progeny (93).…”

Section: Discussionmentioning

confidence: 99%

“…The PLU-1 nuclear protein is expressed in most primary breast cancers and breast cancer cell lines (4,46), while its expression in normal adult tissues is largely restricted to testes (46), where it is expressed in spermatogonia and in specific stages of meiosis (48). However, significant expression is also seen in the murine pregnant mammary gland (4) and in the embryonic mammary bud (4,47).…”

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Functional Analysis of the Transcription Repressor PLU-1/JARID1B

Scibetta

Santangelo

Coleman

et al. 2007

Molecular and Cellular Biology

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The PLU-1/JARID1B nuclear protein, which is upregulated in breast cancers, belongs to the ARID family of DNA binding proteins and has strong transcriptional repression activity. To identify the target genes regulated by PLU-1/JARID1B, we overexpressed or silenced the human PLU-1/JARID1B gene in human mammary epithelial cells by using adenovirus and RNA interference systems, respectively, and then applied microarray analysis to identify candidate genes. A total of 100 genes showed inversely correlated differential expression in the two systems. Most of the candidate genes were downregulated by the overexpression of PLU-1/JARID1B, including the MT genes, the tumor suppressor gene BRCA1, and genes involved in the regulation of the M phase of the mitotic cell cycle. Chromatin immunoprecipitation assays confirmed that the metallothionein 1H (MT1H), -1F, and -1X genes are direct transcriptional targets of PLU-1/JARID1B in vivo. Furthermore, the level of trimethyl H3K4 of the MT1H promoter was increased following silencing of PLU-1/JARID1B. Both the PLU-1/JARID1B protein and the ARID domain selectively bound CG-rich DNA. The GCACA/C motif, which is abundant in metallothionein promoters, was identified as a consensus binding sequence of the PLU-1/ JARID1B ARID domain. As expected from the microarray data, cells overexpressing PLU-1/JARID1B have an impaired G 2 /M checkpoint. Our study provides insight into the molecular function of the breast cancerassociated transcriptional repressor PLU-1/JARID1B.The PLU-1 nuclear protein is expressed in most primary breast cancers and breast cancer cell lines (4, 46), while its expression in normal adult tissues is largely restricted to testes (46), where it is expressed in spermatogonia and in specific stages of meiosis (48). However, significant expression is also seen in the murine pregnant mammary gland (4) and in the embryonic mammary bud (4, 47). Thus, in addition to being elevated in breast cancer, PLU-1 is involved in the development and differentiation of the mammary gland.The PLU-1 gene encodes a 1,544-amino-acid multidomain protein that is exclusively localized to the nucleus. Sequence homology analysis shows that it contains several conserved domains, including the ARID DNA binding domain (AT-richinteracting domain), plant homeodomain/leukemia-associated protein domains (PHD domains), Jumonji domains, and putative nuclear localization signals (46). The ARID domain, the N-terminal and C-terminal Jumonji domains (JmJN and JmJC), two of the plant homeodomain domains, and a novel Trp/Tyr/Phe/Cys domain (the PLU domain), which overlaps the JmJC domain (62), are conserved in the four members of the JARID1 subfamily of the larger family of ARID proteins (15 proteins to date) (86). Although their sequence homology is high, these proteins appear to have diverse functions, with JARID1A (RBP2) being involved in activating transcription from nuclear receptors (14), PLU-1 (now referred to as PLU-1/JARID1B) being a strong transcriptional repressor (75, 88), and JARID1C (the SMCX gene) ...

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Functional Analysis of the Transcription Repressor PLU-1/JARID1B

Scibetta

Santangelo

Coleman

et al. 2007

Molecular and Cellular Biology

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“…However, only JARID1B has been reported to be expressed in cancer. 7,9,11,14 JARID1A shows a wider range of expression, and JARID1C is associated with neural development and X-linked mental retardation. 37 The JARID1B HLA-A*0201 epitopes analyzed here were selected for showing the least conservation between the other JARID1 proteins, and any T cells generated should not react with the other members of the JARID1 family.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10][11] More recently, expression of this gene in other cancers (bladder, lung, AML) has been reported and the restricted expression in normal tissues confirmed 12 suggesting a specific involvement of PLU-1/JAR-ID1B in malignancy. Moreover, the restricted expression in adult tissues makes the protein a potential therapeutic target, particularly in women.…”

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confidence: 87%

T cells reactive with HLA‐A*0201 peptides from the histone demethylase JARID1B are found in the circulation of breast cancer patients

Coleman

Correa

Cooper

et al. 2011

Intl Journal of Cancer

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The nuclear protein PLU-1/JARID1B/KDM5 is widely expressed in breast cancers while showing highly restricted expression in normal adult tissues. To investigate whether JARID1B is a potential target antigen for immunotherapy of breast cancer, we have analyzed the responses of CD8 1 T cells to JARID1B HLA-A*0201 peptides in vitro and used peptide multimers to detect the presence of JARID1B reactive T cells in the circulation of breast cancer patients. Peptides were selected using two webbased algorithms: criteria for inclusion being a high score in both prediction algorithms, and nonhomology with retinoblastoma binding protein-2 (RBP2/JARID1A/KDM5A). A 65-peptide panel was selected and assayed for binding strength by competition assay to obtain the IC 50 . The immunogenicity in vitro of these peptides was assessed by T cell stimulation experiments, using autologous dendritic cells as APCs in the first rounds followed by autologous lymphoblasts. Fourteen of the peptides assayed produced cultures having >2% of the CD8 1 cells being IFN-c 1 after 3-6 rounds of stimulation. An HLA-A*0201 cell line could activate the specific T cells if pulsed with peptide, but endogenous peptide levels were insufficient for activation. Nevertheless, multimer staining of circulating T cells from breast cancer patients showed a significantly higher percentage of multimer positive CD8 1 T cells, as compared to healthy adults for two of three JARID1B epitopes tested. One of these, peptide 73 (QLYALPCVL), was analyzed for memory phenotype, and found to have a significantly higher proportion of central memory T cells than the control group, demonstrating a previous exposure to the peptide.

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Breast cancer associated transcriptional repressor PLU‐1/JARID1B interacts directly with histone deacetylases

Barrett¹,

Santangelo²,

Tan³

et al. 2007

Intl Journal of Cancer

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The PLU-1/JARID1B nuclear protein, which is expressed in a high proportion of breast cancers, but shows restricted expression elsewhere, belongs to the ARID family of proteins, known to play important roles in development, differentiation, transcriptional regulation and chromatin remodeling. PLU-1/JARID1B is a strong transcriptional repressor, and here we show that the protein localizes in MAD bodies when cotransfected with class IIa histone deacetylases (HDACs) or N-CoR. Direct binding to class I and class IIa HDACs is demonstrated, while the interaction with N-CoR appears to be indirect. The domains involved in the HDAC4-PLU-1/JARID1B interaction were investigated in detail, and the data show that 2 PHD domains in PLU-1/JARID1B, which are involved in transcriptional repression, are also crucial for binding to a domain in the 5 0 region of HDAC4, overlapping the MEF-2 binding region. Physiological relevance of this interaction in the mammary gland is suggested from the observation that HDAC4 and PLU-1/JARID1B are coexpressed in the pregnant and involuting mouse mammary gland and are both silenced at lactation. Significantly, the expression of both proteins is seen in breast cancers. ' 2007 Wiley-Liss, Inc.Key words: PLU-1/JARID1B; breast cancer; transcriptional repression; histone deacetylasesThe PLU-1 gene was identified in a differential screen for genes that were down-regulated when HER2 signaling was inhibited. 1 However, PLU-1 has since been demonstrated to be expressed in 90% of breast carcinomas, regardless of the level of HER2 expression, and appears to be associated with malignant progression.2 In normal human adult tissues, the highest levels of expression of PLU-1 mRNA are seen in testis 1,3 with low levels of expression being observed in placenta, lymph node, and thymus.2 In the normal mammary gland, mPlu-1 mRNA is expressed in the embryo in the developing mammary bud, and at pregnancy in the adult, 4 suggesting a role in proliferation in the developing and differentiating tissue.The PLU-1 protein sequence contains several well-conserved domains known to be involved in protein interactions, gene regulation, and chromatin remodeling. These include 3 PHD domains, 5,6 the ARID domain (AT-rich interacting domain), 7 and 2 potential hormone-binding motifs. 8 The novel Trp/Tyr/Cys domain (overlapping the JmjC domain and renamed the PLU domain 9 ) interacts with a conserved motif found in 2 unrelated transcription factors (BF1 and PAX9).10 Thus, the protein could be recruited to DNA directly through the ARID DNA binding domain, or through other transcription factors.Within the larger ARID family of proteins, PLU-1 has been placed in the JARID1 subclass which contains 4 proteins, characterized by the presence of the JmjN and JmjC domains.11 Consequently, PLU-1 is now referred to as PLU-1/JARID1B. The 4 members of the JARID1 subclass show high conservation of sequence, but appear to have different profiles of expression and different functions. The RBBP2 (JARID1A) protein contains the canonical LXCXC domain...

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PLU-1, a transcriptional repressor and putative testis-cancer antigen, has a specific expression and localisation pattern during meiosis

Cited by 43 publications

References 32 publications

Functional Analysis of the Transcription Repressor PLU-1/JARID1B

Functional Analysis of the Transcription Repressor PLU-1/JARID1B

T cells reactive with HLA‐A*0201 peptides from the histone demethylase JARID1B are found in the circulation of breast cancer patients

Breast cancer associated transcriptional repressor PLU‐1/JARID1B interacts directly with histone deacetylases

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