PML4 induces differentiation by Myc destabilization

Buschbeck, Marcus; Uribesalgo, Iris; Ledl, Andreas; Gutiérrez, Arantxa; Minucci, Saverio; Müller, Stefan; Croce, Luciano Di

doi:10.1038/sj.onc.1210128

Cited by 35 publications

(28 citation statements)

References 28 publications

(32 reference statements)

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“…PML-IV is also the only PML isoform that induces premature senescence (Bischof et al, 2002). Additionally, PML-IV is distinct from other PML isoforms for its ability to trigger c-Myc destabilization (Buschbeck et al, 2007). Notably, even though all PML isoforms recruit p53 and CBP to PODs, PML-IV is the only isoform that increases p53 stability through inducing Ser-46 phosphorylation and Lys-382 acetylation on p53 (Bischof et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Selective activation of NFAT by promyelocytic leukemia protein

et al. 2008

Oncogene

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Promyelocytic leukemia (PML) protein is a tumor suppressor with complicated action mechanisms not yet fully understood. In this study, we found that the nuclear factor of activated T cell (NFAT) is an unexpected partner of PML: PML specifically enhanced the transcription activation of NFAT. In PML-null mouse embryonic fibroblasts, no transcription activity of NFAT could be detected. There was a selective requirement of PML isoform in NFAT activation: PML-I and PML-VI, but not PML-IV, increased NFAT transactivation. PML specifically promoted the expression of many, but not all, NFAT-targeted genes. We found a specific binding of PML to NFATc. The interaction of PML with NFATc in vivo was further confirmed by chromatin immunoprecipitation and DNA affinity precipitation assay analysis. The unexpected coupling of PML with NFAT reveals a novel mechanism underlying the diverse physiological functions of PML.

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Section: Discussionmentioning

confidence: 99%

Selective activation of NFAT by promyelocytic leukemia protein

et al. 2008

Oncogene

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“…One of those factors is the PML protein, which has been shown to regulate Myc degradation (25,26) and can be directly regulated by STAT5A or p53 (23,37). PML forms nuclear bodies in which components of the proteasome have been detected (38).…”

Section: Discussionmentioning

confidence: 99%

Myc Down-regulation as a Mechanism to Activate the Rb Pathway in STAT5A-induced Senescence

Mallette

Gaumont-Leclerc

Huot

et al. 2007

Journal of Biological Chemistry

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Senescence is a general antiproliferative program that avoids the expansion of cells bearing oncogenic mutations. We found that constitutively active STAT5A (ca-STAT5A) can induce a p53-and Rb-dependent cellular senescence response. However, ca-STAT5A did not induce p21 and p16INK4a , which are responsible for inhibiting cyclin-dependent protein kinases and engaging the Rb pathway during the senescence response to oncogenic ras. Intriguingly, ca-STAT5A led to a down-regulation of Myc and Myc targets, including CDK4, a negative regulator of Rb. The down-regulation of Myc was in part proteasome-dependent and correlated with its localization to promyelocytic leukemia bodies, which were found to be highly abundant during STAT5-induced senescence. Introduction of CDK4 or Myc bypassed STAT5A-induced senescence in cells in which p53 was also inactivated. These results uncover a novel mechanism to engage the Rb pathway in oncogene-induced senescence and indicate the existence of oncogene-specific pathways that regulate senescence.The Rb (retinoblastoma) family controls cell proliferation by providing a barrier for cell cycle transitions (1). In molecular terms, this barrier consists of repression of the E2F family of transcription factors, which control the synthesis of genes required for cell cycle progression (2). Growth factors activate the cyclin-dependent protein kinase (CDK) 2 -cyclin complexes that phosphorylate Rb, inhibiting its binding to E2F factors (1). Gain-of-function mutations in genes that stimulate cell cycle progression can potentially disable the Rb barrier, leading to tumorigenesis. Hence, for efficient tumor suppression, normal cells must avoid Rb inactivation by oncogenes. Studies on the senescent cell cycle arrest in response to oncogenic ras have provided a general model of Rb activation by oncogenes in normal cells. Aberrant ras activity induces the expression of CDK inhibitors of the INK4 family such as p15INK4b (3) (6). This allele was shown to be constitutively phosphorylated at tyrosine residues, localized to the nucleus, and transcriptionally active (7). Hence, ca-STAT5A provides a persistent and unregulated STAT5A signal similar to that observed in some human tumors (8, 9). We show here that ca-STAT5A engages the Rb pathway by down-regulating Myc instead of the p16 INK4a -mediated mechanism described in RasV12-induced senescence. As a consequence, cells expressing ca-STAT5 have a decrease in the expression of Myc targets such as CDK4 and an increase in the CDK inhibitor p15 INK4b. In agreement, ca-STAT5A-induced senescence is blocked when CDK4 or Myc is overexpressed in combination with dominant-negative p53 or the E6 protein of human papillomavirus. We conclude that the pathways regulating Rb by oncogenic signals are oncogene-specific and discuss the relevance of this concept for human cancers. EXPERIMENTAL PROCEDURESCells and Retroviruses-Normal human diploid fibroblasts (HDFs), BJ cells (obtained from Dr. S. W. Lowe), and IMR90 cells (American Type Culture Collection) were cultured in...

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“…The mechanistic details of this tumor-suppression pathway will be the focus of future studies, but it can be anticipated that it involves novel functions of the ubiquitindependent proteasome pathway (9) and a tumor-suppressive role for E3 ligases mediating the recognition of phosphorylated proteins. Of note, PML, which is important for OIS, plays a role in the degradation of MYC (76) and could be implicated in the degradation of other targets of the SAPD.…”

Section: Erks Protein Degradation and Tumor Suppressionmentioning

confidence: 99%