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

K. Petrie, F. Guidez, J. Zhu, L. Howell, G. Owen, Y. P. Chew, S. Parks, S. Waxman, J. Licht, S. Mittnacht, Arthur Z Zelent

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Translocations of the retinoic acid receptor-α (RARα) locus with the promyelocytic leukemia zinc-finger (PLZF) or PML genes lead to expression of oncogenic PLZF-RARα or PML-RARα fusion proteins, respectively. These fusion oncoproteins constitutively repress RARα target genes, in large part through aberrant recruitment of multiprotein co-repressor complexes. PML and PML-RARα 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.

Original languageEnglish (US)
Pages (from-to)5260-5266
Number of pages7
JournalOncogene
Volume27
Issue number39
DOIs
StatePublished - Sep 4 2008
Externally publishedYes

Fingerprint

Retinoblastoma Protein
Zinc Fingers
Retinoblastoma
Leukemia
Transcription Factors
Genes
Retinoic Acid Receptors
Retinoblastoma Genes
Stem Cells
Poxviridae
Tumor Suppressor Proteins
Multiprotein Complexes
Co-Repressor Proteins
Proteins
Chromatin Immunoprecipitation
Oncogene Proteins
S Phase
Genetic Promoter Regions
Cell Biology

Keywords

  • E2F1
  • PLZF
  • Rb

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Petrie, K., Guidez, F., Zhu, J., Howell, L., Owen, G., Chew, Y. P., ... Zelent, A. Z. (2008). Retinoblastoma protein and the leukemia-associated PLZF transcription factor interact to repress target gene promoters. Oncogene, 27(39), 5260-5266. https://doi.org/10.1038/onc.2008.159

Retinoblastoma protein and the leukemia-associated PLZF transcription factor interact to repress target gene promoters. / Petrie, K.; Guidez, F.; Zhu, J.; Howell, L.; Owen, G.; Chew, Y. P.; Parks, S.; Waxman, S.; Licht, J.; Mittnacht, S.; Zelent, Arthur Z.

In: Oncogene, Vol. 27, No. 39, 04.09.2008, p. 5260-5266.

Research output: Contribution to journalArticle

Petrie, K, Guidez, F, Zhu, J, Howell, L, Owen, G, Chew, YP, Parks, S, Waxman, S, Licht, J, Mittnacht, S & Zelent, AZ 2008, 'Retinoblastoma protein and the leukemia-associated PLZF transcription factor interact to repress target gene promoters', Oncogene, vol. 27, no. 39, pp. 5260-5266. https://doi.org/10.1038/onc.2008.159
Petrie, K. ; Guidez, F. ; Zhu, J. ; Howell, L. ; Owen, G. ; Chew, Y. P. ; Parks, S. ; Waxman, S. ; Licht, J. ; Mittnacht, S. ; Zelent, Arthur Z. / Retinoblastoma protein and the leukemia-associated PLZF transcription factor interact to repress target gene promoters. In: Oncogene. 2008 ; Vol. 27, No. 39. pp. 5260-5266.
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abstract = "Translocations of the retinoic acid receptor-α (RARα) locus with the promyelocytic leukemia zinc-finger (PLZF) or PML genes lead to expression of oncogenic PLZF-RARα or PML-RARα fusion proteins, respectively. These fusion oncoproteins constitutively repress RARα target genes, in large part through aberrant recruitment of multiprotein co-repressor complexes. PML and PML-RARα 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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