Plzf Mediates Transcriptional Repression of HoxD Gene Expression through Chromatin Remodeling

Barna, Maria; Merghoub, Taha; Costoya, José A.; Ruggero, Davide; Branford, Matthew; Bergia, Anna; Samorı̀, Bruno; Pandolfi, Pier Paolo

doi:10.1016/s1534-5807(02)00289-7

Cited by 158 publications

(134 citation statements)

References 52 publications

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“…A balance between activating signal and transcriptional repressors, represented by retinoic acid and PLZF, regulates HoxD gene expression boundaries in the limb bud (Barna et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Role of PLZF in melanoma progression

et al. 2004

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The promyelocytic leukemia zinc finger (PLZF) protein has been described as a transcriptional repressor of homeobox (HOX)-containing genes during embryogenesis. As we previously demonstrated a functional link between overexpression of HOXB7 and melanoma progression, we investigated the lack of PLZF as the possible cause of HOXB7 constitutive activation in these neoplastic cells. Accordingly, we found PLZF expression in melanocytes, but not in melanoma cells, a pattern inversely related to that of HOXB7. PLZF retroviral gene transduction was then performed in a panel of melanoma cell lines, and tumorigenicity was compared with that of empty vector-transduced control cell lines. Evaluation of in vitro migration, invasion and adhesion indicated that PLZF gene transduction induced a less malignant phenotype, as confirmed through in vivo studies performed in athymic nude mice. This reduced tumorigenicity was not coupled with HOXB7 repression. In order to find more about the molecular targets of PLZF, the gene expression profiles of PLZF-and empty vector-transduced A375 melanoma cells were analysed by Atlas Cancer macroarray. Among several genes modulated by PLZF enforced expression, of particular interest were integrin avb3, osteonectin/SPARC and matrix metalloprotease-9 that were downmodulated, and the tyrosinase-related protein-1 that was upregulated in all the analysed samples. This profile confirms the reduced tumorigenic phenotype with reversion to a more differentiated, melanocyte like, pattern, thus suggesting a suppressor role for PLZF in solid tumors. Moreover, these results indicate that PLZF and HOXB7 are functionally independent and that their coupled deregulation may account for most of the alterations described in melanomas.

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“…A balance between activating signal and transcriptional repressors, represented by retinoic acid and PLZF, regulates HoxD gene expression boundaries in the limb bud (Barna et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Role of PLZF in melanoma progression

et al. 2004

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“…The induced hypermethylation is linked to oncogenesis and treatment with retinoic acid reverses the transformed phenotype through the induction of target gene demethylation and re-expression. The promyelocytic leukemia zinc finger (PLZR) protein also associates with transcriptional repressors such as HDACs and PcG proteins (Barna et al 2002) and the PLZR-RAR␣ fusion likewise represses genes normally activated by RAR␣. In contrast to PML-RAR␣ fusions, PLZR-RAR␣ target genes are insensitive to retinoic acid treatments, despite the fact that retinoic acid does induce PLZR-RAR␣ degradation (Rego et al 2000).…”

Section: Integrative Epigenetics: the Achilles' Heelmentioning

confidence: 99%

Epigenetics and cancer

Lund¹,

Lohuizen²

2004

Genes Dev.

442

318

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Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation locally and globally via modifications of the DNA and by modification or rearrangement of nucleosomes. Epigenetic gene regulation collaborates with genetic alterations in cancer development. This is evident from every aspect of tumor biology including cell growth and differentiation, cell cycle control, DNA repair, angiogenesis, migration, and evasion of host immunosurveillance. In contrast to genetic cancer causes, the possibility of reversing epigenetic codes may provide new targets for therapeutic intervention.Epigenetic programming is crucial in mammalian development, and stable inheritance of epigenetic settings is essential for the maintenance of tissue-and cell-typespecific functions (Li 2002). With the exception of controlled genomic rearrangements, such as those of the immunoglobulin and T-cell receptor genes in B and T cells, all other differentiation processes are initiated or maintained through epigenetic processes. Not surprisingly therefore, epigenetic gene regulation is characterized overall by a high degree of integrity and stability. Evidence is accumulating that suggests that the intrinsic stability is caused by multiple interlocking feedback mechanisms between functionally unrelated epigenetic layers, such as DNA methyltransferases (DNMTs) and histone modifying enzymes, resulting in the stable commitment of a locus to a particular activity state. In somatic cells, the transcriptional status of most genes is epigenetically fixed. However, other genes, such as cell cycle checkpoint genes and genes directly affected by exogenous stimuli such as growth factors or cell-cell contact, likely reside in a balanced state sensitive to dynamic adjustments in histone modifications, thereby allowing for rapid responses to specific stimuli. Perturbation of epigenetic balances may lead to alterations in gene expression, ultimately resulting in cellular transformation and malignant outgrowth; the involvement of deregulated epigenetic mechanisms in cancer development has received increased attention in recent years.Per definition, epigenetic regulators alter the activities and abilities of a cell without directly affecting and mutating the sequence of the DNA. In this review, we deal with epigenetic gene regulation as imposed by DNA methylation, covalent modifications of the canonical core histones, deposition of variant histone proteins, local nucleosome remodeling, and long-range epigenetic regulators. Understanding the molecular details behind "epigenetic cancer diseases" holds potentially important prospects for medical treatment, as it allows for novel strategies for drug development. A number of recent reviews have provided details on epigenetic mechanisms and their involvement in cancer, and we refer to these for more in-depth information on individual epigenetic mechanisms

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“…Labeling proceeded for 4 h, starting 48 h after transfection (COS cells). Protein extracts were prepared and used for immunoprecipitation using PLZF polyclonal antibody as described (Barna et al, 2002). Immunoprecipitated protein was resolved on a 7.5% SDS-PAGE, blotted onto Protan (S&S, New Jersey, NJ, USA) and visualized by autoradiography.…”

Section: Purification Of Gst Fusion Proteinsmentioning

confidence: 99%

“…The PLZF gene encodes a highly conserved transcriptional repressor defined by the presence of a poxvirus and zinc-finger domain (POZ) at its N terminus, responsible for homodimerization and recruitment of transcriptional co-repressors, and nine Kru¨ppel-type C 2 H 2 zinc fingers located at the C terminus involved in binding to sequence-specific DNA sites. Besides having critical developmental functions (Barna et al, 2000(Barna et al, , 2002, PLZF is abundantly expressed in stem/progenitor cells of both the hematopoietic and male germ cell compartments and its expression levels decline upon differentiation suggesting that its downregulation may be required for the onset of terminal differentiation (Reid et al, 1995;Buaas et al, 2004;Costoya et al, 2004;Filipponi et al, 2007). The biological roles of PLZF are likely to be associated with its potent growth-suppressive effects.…”

Section: Introductionmentioning

confidence: 99%