The Krüppel-like zinc-finger protein ZNF224 represses aldolase A gene transcription by interacting with the KAP-1 co-repressor protein

Medugno, L.; Florio, Francesca; Cegli, Rossella De; Grosso, Michela; Lupo, Angelo; Costanzo, Paola; Izzo, Paola

doi:10.1016/j.gene.2005.06.021

Cited by 35 publications

(44 citation statements)

References 31 publications

(45 reference statements)

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“…6C, middle panel). In contrast, endogenous aldolase A promoter, which is regulated by KAP1 but not Pax3 (26), showed no detectable binding of Pax3 or HDAC10 (Fig. 6C, bottom panel).…”

Section: Hdac10 Relieves Repression Of the Melanogenesis Program-pax3mentioning

confidence: 96%

Histone Deacetylase 10 Relieves Repression on the Melanogenic Program by Maintaining the Deacetylation Status of Repressors

Lai

Lin

Yao

et al. 2010

Journal of Biological Chemistry

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HDAC10 belongs to the class II histone deacetylase family; however, its functions remain enigmatic. We report here that the HDAC10 protein complex contained deacetylated chaperone protein hsc70, and HDAC10 relieved repression of melanogenesis by decreasing the repressional activity of two transcriptional regulators, paired box protein 3 (Pax3) and KRAB-associated protein 1 (KAP1). HDAC10 physically interacted with Pax3 and KAP1 in a ternary complex and maintained Pax3 and KAP1 in a deacetylated state. Deacetylated Pax3 and KAP1 derepressed promoters of microphthalmia-associated transcription factor (MITF) and melanocyte-specific tyrosinase-related protein 1 and 2 (TRP-1 and TRP-2), three genes of the melanogenesis cascade, in a trichostatin A-sensitive manner. Co-occupancy of melanogenic promoters by HDAC10, Pax3, and KAP1 only happened in cells of the melanocyte lineage, and KAP1 facilitated nuclear enrichment of HDAC10. Finally, cellular melanin content correlated directly with the expression level and activity of HDAC10. Our results not only show that HDAC10 regulates melanogenesis but also demonstrate that the transcriptional activities of Pax3 and KAP1 are intimately linked to their acetylation status.It is well established that histone acetyltransferases and histone deacetylases (HDACs) 3 dynamically modify the N termini of core histones, change the chromatin structure, and modulate transcription. Histone acetyltransferases transfer acetyl groups from acetyl-CoA to the ⑀-amino group of lysine residues, thereby neutralizing the positive charge of the histone tails and decreasing their affinity for DNA. HDACs, in contrast, catalyze the hydrolysis of N-acetyllysines and restore the positive charge Previous reports demonstrated that histone acetyltransferases/HDACs modify not only core histones but also nonhistone proteins, most of which are transcription factors (for review, see 4). Acetylation/deacetylation of transcription factors may affect their DNA-binding activities, protein stability, or protein-protein interactions, thereby contributing to proper transcriptional regulation.HDAC10 is a member of the class II HDAC family (5-8). The expression level of HDAC10 decreases in patients with lung cancer (9), suggesting that HDAC10 is important for maintaining the normal behavior of cells. Although HDAC10 represses transcription when tethered to a target promoter, a fundamental understanding of the function of HDAC10 remains elusive. In this report, we show that HDAC10 interacted with nonhistone proteins and kept them in a deacetylated form. Deacetylated heat shock protein 70 was a component of the HDAC10 stable protein complex. More important, in cells of melanogenic lineage, deacetylated paired box protein 3 (Pax3) and Krüppel-associated box (KRAB)-associated protein 1 (KAP1) derepressed promoters of microphthalmia-associated transcription factor (MITF) and melanocyte-specific tyrosinase-related protein 1 and 2 (TRP-1 and TRP-2), three genes that control the melanogenesis program. HDAC10 not only formed a ter...

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“…6C, middle panel). In contrast, endogenous aldolase A promoter, which is regulated by KAP1 but not Pax3 (26), showed no detectable binding of Pax3 or HDAC10 (Fig. 6C, bottom panel).…”

Section: Hdac10 Relieves Repression Of the Melanogenesis Program-pax3mentioning

confidence: 96%

Histone Deacetylase 10 Relieves Repression on the Melanogenic Program by Maintaining the Deacetylation Status of Repressors

Lai

Lin

Yao

et al. 2010

Journal of Biological Chemistry

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“…In human cells, ZNF224 is associated with glycolysis and oxidative metabolism (Iacobazzi et al, 2009;Lupo et al, 2011). The mechanism of action of these KRAB-ZFPs are not all defined, but they most likely act via KAP1 as ZNF224, for instance, was shown to interact with the co-repressor (Medugno et al, 2005). Furthermore, KAP1 plays important roles in the liver: liver-specific KAP1 knockout leads to male-restricted hepatic carcinogenesis and perturbs the metabolism of hormones and antibiotics in the liver .…”

Section: Krab-zfps and Metabolismmentioning

confidence: 99%

KRAB zinc finger proteins

2017

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Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs) are the largest family of transcriptional regulators in higher vertebrates. Characterized by an N-terminal KRAB domain and a C-terminal array of DNA-binding zinc fingers, they participate, together with their co-factor KAP1 (also known as TRIM28), in repression of sequences derived from transposable elements (TEs). Until recently, KRAB-ZFP/KAP1-mediated repression of TEs was thought to lead to irreversible silencing, and the evolutionary selection of KRAB-ZFPs was considered to be just the host component of an arms race against TEs. However, recent advances indicate that KRAB-ZFPs and their TE targets also partner up to establish speciesspecific regulatory networks. Here, we provide an overview of the KRAB-ZFP gene family, highlighting how its evolutionary history is linked to that of TEs, and how KRAB-ZFPs influence multiple aspects of development and physiology.

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“…The annotation of the three identified proteins is summarized in Table 1. Based on protein functions determined using information from the Swiss-Prot database, the identified proteins associated with a response to SD were involved in cell cycle regulation, signal transduction, and metabolism [18][19][20] , which suggested that the enrichment of these proteins in SD MVs was involved in myeloma progression.…”

Section: Wwwnaturecom/aps Sun L Et Almentioning

confidence: 99%

Serum deprivation elevates the levels of microvesicles with different size distributions and selectively enriched proteins in human myeloma cells in vitro

et al. 2013

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Aim: To investigate the effects of serum deprivation (SD) on microvesicles (MVs) secreted from human myeloma cells and the implications for disease progression. Methods: RPMI 8226, U266, and KM3 human myeloma cells were incubated in medium containing 10% (non-SD) or 1% fetal bovine serum (SD) and MVs were isolated. The levels and size distribution of MVs were analyzed with flow cytometry. The protein profiles of MVs were studied using 2D SDS-PAGE, MALDI-TOF-MS, and Western blotting. NF-κB activation was analyzed using EMSA. Angiogenesis was examined in Eahy926 endothelial cells. Results: Exposure of RPMI 8226 cells to SD for 24 h did not alter the number of apoptotic cells. However, SD increased the number of MVs from RPMI 8226, U266, and KM3 cells to 2.5-, 4.3-, and 3.8-fold, respectively. The size distribution of SD MVs was also significantly different from that of non-SD MVs. Three proteins ZNF224, SARM, and COBL in SD MVs were found to be up-regulated, which were involved in cell cycle regulation, signal transduction and metabolism, respectively. Co-culture of SD MVs and RPMI 8226 cells increased NF-κB activation in the target RPMI 8226 cells. Furthermore, SD MVs from RPMI 8226 cells significantly increased the microtubule formation capacity of Eahy926 endothelial cells compared with non-SD MVs. Conclusion: SD elevates the levels of microvesicles with different size distribution and selectively enriched proteins in human myeloma cells in vitro. The selectively enriched proteins, especially ZNF224, may play key roles in regulation of myeloma cells, allowing better adaptation to SD.

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The Krüppel-like zinc-finger protein ZNF224 represses aldolase A gene transcription by interacting with the KAP-1 co-repressor protein

Cited by 35 publications

References 31 publications

Histone Deacetylase 10 Relieves Repression on the Melanogenic Program by Maintaining the Deacetylation Status of Repressors

Histone Deacetylase 10 Relieves Repression on the Melanogenic Program by Maintaining the Deacetylation Status of Repressors

KRAB zinc finger proteins

Serum deprivation elevates the levels of microvesicles with different size distributions and selectively enriched proteins in human myeloma cells in vitro

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