Expression and role of PML gene in normal adult hematopoiesis: functional interaction between PML and Rb proteins in erythropoiesis

Labbaye, Catherine; Valtieri, Mauro; Grignani, Francesco; Puglisi, Rossella; Luchetti, Luisella; Masella, B.; Alcalay, Myriam; Testa, Ugo; Peschle, Cesare

doi:10.1038/sj.onc.1202682

Cited by 23 publications

(33 citation statements)

References 65 publications

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“…Similar observations were also made in the erythroid leukemia cell line (HEL) (Figure 5d, right panel), which spontaneously expresses both PLZF and GATA1 proteins at levels detectable by Western blot analysis (Fig. 5b, Right panel).The specificity of PLZF/GATA1 complex was confirmed in control experiments performed by immunoprecipitation of PLZF and pRb105 proteins (Labbaye et al, 1999). No PLZF/pRb105 complex was detected in TF1-PLZF cells (data not shown).…”

Section: Exogenous Plzf Induces Mk Differentiation In the Tf1 Cell Linesupporting

confidence: 67%

“…Under appropriate serumfree culture conditions, HPCs undergo unilineage differentiation and maturation along the erythroid (E), granulocytic (G) or MK pathway: in these culture systems, 495% of the cells pertain to a single lineage (Labbaye et al, 1995(Labbaye et al, , 1999Guerriero et al, 1995;Testa et al, 1996).…”

Section: Expression Of Plzf Mrna In Unilineage Hematopoietic Progenitmentioning

confidence: 99%

“…Human hematopoietic progenitor cells (HPCs) were purified from adult peripheral blood according to previously reported procedures (Gabbianelli et al, 1990;Labbaye et al, 1999). Under appropriate serumfree culture conditions, HPCs undergo unilineage differentiation and maturation along the erythroid (E), granulocytic (G) or MK pathway: in these culture systems, 495% of the cells pertain to a single lineage (Labbaye et al, 1995(Labbaye et al, , 1999Guerriero et al, 1995;Testa et al, 1996).…”

Section: Expression Of Plzf Mrna In Unilineage Hematopoietic Progenitmentioning

confidence: 99%

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PLZF induces megakaryocytic development, activates Tpo receptor expression and interacts with GATA1 protein

et al. 2002

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We investigated the expression of the PLZF gene in purified human hematopoietic progenitors induced to unilineage erythroid, granulocytic or megakaryocytic differentiation and maturation in serum-free culture. PLZF is expressed in quiescent progenitors: the expression level progressively rises through megakaryocytic development, whereas it gradually declines in erythroid and granulopoietic culture. To investigate the role of PLZF in megakaryopoiesis, we transduced the PLZF gene into the erythro-megakaryocytic TF1 cell line. PLZF overexpression upmodulates the megakaryocytic specific markers (CD42a, CD42b, CD61, PF4) and induces the thrombopoietin receptor (TpoR). The proximal promoter of the TpoR gene is activated in PLZF-expressing TF1 cells: in this promoter region, a PLZF DNA-binding site was identified by deletion constructs studies. Interestingly, PLZF and GATA1 proteins coimmunoprecipitate in PLZF-expressing TF1 cells: enforced expression of both PLZF and GATA1 in TF1 cells results in increased upregulation of megakaryocytic markers, as compared to exogenous PLZF or GATA1 alone, suggesting a functional role for the PLZF/GATA1 complex. Our data indicate that PLZF plays a significant stimulatory role in megakaryocytic development, seemingly mediated in part by induction of TpoR expression at transcriptional level. This stimulatory effect is potentiated by physical interaction of PLZF and GATA1, which are possibly assembled in a multiprotein transcriptional complex.

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Section: Exogenous Plzf Induces Mk Differentiation In the Tf1 Cell Linesupporting

confidence: 67%

Section: Expression Of Plzf Mrna In Unilineage Hematopoietic Progenitmentioning

confidence: 99%

Section: Expression Of Plzf Mrna In Unilineage Hematopoietic Progenitmentioning

confidence: 99%

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PLZF induces megakaryocytic development, activates Tpo receptor expression and interacts with GATA1 protein

et al. 2002

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“…In humans, 66% of AML and 79% of CML patients exhibit reduced levels of IRF-8 or no expression at all. PML modulates key tumor suppressor genes such as p53 and the retinoblastoma gene, and consequently PML KO mice are tumor-prone (52,53). Furthermore, PML-RAR␣ is thought to act as a dominant negative of PML, thereby promoting APL.…”

Section: Discussionmentioning

confidence: 99%

Interferon Regulatory Factor-8 Is Indispensable for the Expression of Promyelocytic Leukemia and the Formation of Nuclear Bodies in Myeloid Cells

Dror

Rave-Harel

Burchert

et al. 2007

Journal of Biological Chemistry

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Interferon (IFN) regulatory factor-8 (IRF-8), previously known as ICSBP, is a myeloid cell essential transcription factor. Mice with null mutation in IRF-8 are defective in the ability of myeloid progenitor cells to mature toward macrophage lineage. Accordingly, these mice develop chronic myelogenous leukemia (CML). We demonstrate here that IRF-8 is an obligatory regulator of the promyelocytic leukemia (PML) gene in activated macrophages, leading to the expression of the PML-I isoform. This regulation is most effective together with two other transcription factors, IRF-1 and PU.1. PML is a tumor suppressor gene that serves as a scaffold protein for nuclear bodies. IRF-8 is not only essential for the IFN-␥-induced expression of PML in activated macrophages but also for the formation of nuclear bodies. Reduced IRF-8 transcript levels were reported in CML patients, and a recovery to normal levels was observed in patients in remission following treatment with IFN-␣. We demonstrate a significant correlation between the levels of IRF-8 and PML in these CML patients. Together, our results indicate that some of the myeloleukemia suppressor activities of IRF-8 are mediated through the regulation of PML. When IRF-8 levels are compromised, the reduced PML expression may lead to genome instability and eventually to the leukemic phenotype.

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“…Given the documented interaction of PML and PMLRARa with Rb (Alcalay et al, 1998;Labbaye et al, 1999;Khan et al, 2001), we sought to investigate whether PLZF and PLZF-RARa also associated with this transcriptional repressor. Pull-down assays using bacterially expressed GST-Rb or GST-PLZF and These test proteins were then used in pull-down assays with GST-Rb.…”

mentioning

confidence: 99%

Retinoblastoma protein and the leukemia-associated PLZF transcription factor interact to repress target gene promoters

et al. 2008

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Translocations of the retinoic acid receptor-a (RARa) locus with the promyelocytic leukemia zinc-finger (PLZF) or PML genes lead to expression of oncogenic PLZFRARa or PML-RARa fusion proteins, respectively. These fusion oncoproteins constitutively repress RARa target genes, in large part through aberrant recruitment of multiprotein co-repressor complexes. PML and PMLRARa have previously been shown to associate with the retinoblastoma (Rb) tumour suppressor protein in its hypophosphorylated state. Here, we demonstrate that PLZF also interacts with Rb in vitro and in vivo. The interaction between PLZF and Rb is mediated through the Rb pocket and the region of PLZF that lies between its transcriptional repression (poxvirus and zinc-finger, POZ) and DNA-binding (zinc-finger) domains. In addition, Rb can simultaneously interact with PLZF and the E2F1 S phase-inducing transcription factor, suggesting that these proteins can exist in the same multiprotein complex. In contrast to the interaction of Rb with PML or E2F1, the PLZF-Rb interaction is not dependent on hypophosphorylation of Rb. These data are supported by chromatin immunoprecipitation analysis, which indicates that PLZF associates with the promoter region of CDC6, a known E2F/Rb target gene. Co-expression of PLZF and Rb results in enhancement of transcriptional repression of PLZF and E2F/Rb target genes, indicating functional co-operation between the two proteins. Both PLZF and Rb have been shown to function in stem cells and taken together these data suggest that interactions between PLZF and Rb could be important in stem cell biology.

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Expression and role of PML gene in normal adult hematopoiesis: functional interaction between PML and Rb proteins in erythropoiesis

Cited by 23 publications

References 65 publications

PLZF induces megakaryocytic development, activates Tpo receptor expression and interacts with GATA1 protein

PLZF induces megakaryocytic development, activates Tpo receptor expression and interacts with GATA1 protein

Interferon Regulatory Factor-8 Is Indispensable for the Expression of Promyelocytic Leukemia and the Formation of Nuclear Bodies in Myeloid Cells

Retinoblastoma protein and the leukemia-associated PLZF transcription factor interact to repress target gene promoters

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