Nuclear localization signal region in nuclear receptor PXR governs the receptor association with mitotic chromatin

Rana, Manjul; Dash, Amit Kumar; Ponnusamy, Kalaiarasan; Tyagi, Rakesh K.

doi:10.1007/s10577-018-9583-2

Cited by 19 publications

(14 citation statements)

References 64 publications

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“…We next questioned what prevents Halo-HSF2 from this coating behavior. Previous studies have shown that, despite disassembly of the nuclear envelope during mitosis, the nuclear localization signal (NLS) and the nuclear import mechanism play a role in localizing proteins to mitotic chromosomes (10, 25, 53). One possibility is that the NLS within HSF2 is insufficient to enforce coating of mitotic DNA.…”

Section: Resultsmentioning

confidence: 99%

Distinct modes of heat shock transcription factor interactions with mitotic chromosomes

Price

Budzyński

Shen

et al. 2022

Preprint

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A large number of transcription factors have been shown to bind and interact with mitotic chromosomes, which may promote the efficient reactivation of transcriptional programs following cell division. Although the DNA-binding domain (DBD) contributes strongly to TF behavior, TFs from the same DBD family can display distinct binding behaviors during mitosis. To define the mechanisms governing TF behavior during mitosis in mouse embryonic stem cells, we examined two related TFs: Heat Shock Factor 1 and 2 (HSF1 and HSF2). We found that HSF2 maintains site-specific binding genome-wide during mitosis, whereas HSF1 binding is globally decreased. Surprisingly, live-cell imaging shows that both factors appear excluded from mitotic chromosomes, and are similarly more dynamic in mitosis than in interphase. Exclusion from mitotic DNA is not due to extrinsic factors like nuclear import and export mechanisms. Rather, we found that the HSF2 DBD alone can coat mitotic chromosomes, but is insufficient to promote HSF1 coating. These data further confirm that site-specific binding and chromosome coating are independent properties, and that for some TFs, mitotic behavior is largely determined by the non-DBD regions.

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Section: Resultsmentioning

confidence: 99%

Distinct modes of heat shock transcription factor interactions with mitotic chromosomes

Price

Budzyński

Shen

et al. 2022

Preprint

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“…Nonetheless, the mechanisms that PXR confreres multidrug resistance are not limited to transcriptional upregulation of MDR1, MRP2 and BCRP, as evidenced that SFN metabolites overcome paclitaxel resistance through microtubular disruption. The finding provokes our attention that PXR governs the receptor interaction with mitotic chromatin and the nuclear localization signal (NLS) (R66-76R) region of PXR is essential for this process [28]. It is worth to note that some SNPs also influence mitotic binding of PXR.…”

Section: Discussionmentioning

confidence: 99%

“…There is a bidirectional nuclear localization sequence (NLS) and two zinc finger structures: CX2CX13CX2C (zinc finger I) and CX5CX9CX2C (zinc finger II) in the DBD region, which is quite similar as that of peroxisome proliferator-activated receptor γ (PPARγ) [27] (Figure 2B). Each zinc finger structure consists of four cysteine residuals that chelate a zinc ion [13,27,28]. The ligand binding domain (LBD) of PXR is composed of a seven-member α-helical sandwich, assembled in three layers with an antiparallel five-strand β sheet spherical structure, which accommodates more ligands in this region [29].…”

Section: The Structure Of the Pxr Proteinmentioning

confidence: 99%

Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance

Niu¹,

Wu²,

Li³

et al. 2022

Int. J. Biol. Sci.

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Pregnane x receptor (PXR) as a nuclear receptor is well-established in drug metabolism, however, it has pleiotropic functions in regulating inflammatory responses, glucose metabolism, and protects normal cells against carcinogenesis. Most studies focus on its transcriptional regulation, however, PXR can regulate gene expression at the translational level. Emerging evidences have shown that PXR has a broad protein-protein interaction network, by which is implicated in the cross signaling pathways. Furthermore, the interactions between PXR and some critical proteins (e.g., p53, Tip60, p300/CBP-associated factor) in DNA damage pathway highlight its potential roles in this field. A thorough understanding of how PXR maintains genome stability and prevents carcinogenesis will help clinical diagnosis and finally benefit patients. Meanwhile, due to the regulation of CYP450 enzymes CYP3A4 and multidrug resistance protein 1 (MDR1), PXR contributes to chemotherapeutic drug resistance. It is worthy of note that the co-factor of PXR such as RXRα, also has contributions to this process, which makes the PXR-mediated drug resistance more complicated. Although single nucleotide polymorphisms (SNPs) vary between individuals, the amino acid substitution on exon of PXR finally affects PXR transcriptional activity. In this review, we have summarized the updated mechanisms that PXR protects the human body against carcinogenesis, and major contributions of PXR with its co-factors have made on multidrug resistance. Furthermore, we have also reviewed the current promising antagonist and their clinic applications in reversing chemoresistance. We believe our review will bring insight into PXR-targeted cancer therapy, enlighten the future study direction, and provide substantial evidence for the clinic in future.

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“…PPARγ contains two C4-type Zn finger domains in the DBD ( 38 ), in which a region between amino acid residues 139 and 198 (between the Znf1 and Znf2) is identified to be homologous to the RING domain, which mediated ubiquitination and degradation of NF-κB/p65 ( 34 ). Likewise, The DBD of human PXR also consists of two C4-type Zn finger domains in the DBD, CX2CX13CX2C (Zn finger I) and CX5CX9CX2C (Zn finger II) ( 39 ). However, whether the Zn fingers in the DBD of PXR contain the E3 ligase activity remains to be elusive.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Receptor PXR Confers Irradiation Resistance by Promoting DNA Damage Response Through Stabilization of ATF3

Niu

Cui

et al. 2022

Front. Oncol.

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Low response rate to radiotherapy remains a problem for liver and colorectal cancer patients due to inappropriate DNA damage response in tumors. Here, we report that pregnane X receptor (PXR) contributes to irradiation (IR) resistance by promoting activating transcription factor 3 (ATF3)-mediated ataxia-telangiectasia-mutated protein (ATM) activation. PXR stabilized ATF3 protein by blocking its ubiquitination. PXR–ATF3 interaction is required for regulating ATF3, as one mutant of lysine (K) 42R of ATF3 lost binding with PXR and abolished PXR-reduced ubiquitination of ATF3. On the other hand, threonine (T) 432A of PXR lost binding with ATF3 and further compromised ATM activation. Moreover, the PXR–ATF3 interaction increases ATF3 stabilization through disrupting ATF3–murine double minute 2 (MDM2) interaction and negatively regulating MDM2 protein expression. PXR enhanced MDM2 auto-ubiquitination and shortened its half-life, therefore compromising the MDM2-mediated degradation of ATF3 protein. Structurally, both ATF3 and PXR bind to the RING domain of MDM2, and on the other hand, MDM2 binds with PXR on the DNA-binding domain (DBD), which contains zinc finger sequence. Zinc finger sequence is well known for nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) playing E3 ligase activity to degrade nuclear factor κB (NFκB)/p65. However, whether zinc-RING sequence grants E3 ligase activity to PXR remains elusive. Taken together, these results provide a novel mechanism that PXR contributes to IR resistance by promoting ATF3-mediated ATM activation through stabilization of ATF3. Our result suggests that targeting PXR may sensitize liver and colon cancer cells to IR therapy.

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Nuclear localization signal region in nuclear receptor PXR governs the receptor association with mitotic chromatin

Cited by 19 publications

References 64 publications

Distinct modes of heat shock transcription factor interactions with mitotic chromosomes

Distinct modes of heat shock transcription factor interactions with mitotic chromosomes

Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance

Nuclear Receptor PXR Confers Irradiation Resistance by Promoting DNA Damage Response Through Stabilization of ATF3

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