CDK9 and SPT5 proteins are specifically required for expression of herpes simplex virus 1 replication-dependent late genes

Zhao, Zhiyuan; Tang, Ka-Wei; Muylaert, Isabella; Samuelsson, Tore; Elias, Per

doi:10.1074/jbc.m117.806000

Cited by 14 publications

(9 citation statements)

References 58 publications

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“…Conversely, we have demonstrated that FIT-039 shows selective inhibition of CDK9 by targeting the ATP-binding pocket, achieving antiviral activity against multiple viruses without major toxicity to host cells (17)(18)(19). These data indicate that, as seen for HPV (26)(27)(28), the P-TEFb complex (CDK9 and cyclin T) plays a major role in viral promoter activity in multiple viral species (39)(40)(41)(42)(43)(44)(45). The ability of FIT-039 to target viral promoter activities prompted us to test its effect on a tumor virus, in which expression of specific viral genes per se is an inducer of transformation and/or malignant progression (19).…”

Section: Discussionmentioning

confidence: 80%

“…Past studies indicated CDK9, over the other CDKs, is prone to be recruited to viral promoters, in association and/or cooperation with viral proteins (39-45), which we consider the mechanical background of the common antiviral effect of FIT-039. For instance, ICP22 of human simplex herpesvirus (HSV) forms complex with CDK9 and SPT5 to activate HSV-1 late gene promoter (40,41), as well as upregulating other HSV-1 transcripts (42). Regarding EB virus (EBV), P-TEFb is required for EBNA2-dependent transcripts, and CDK9 inhibition by 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole has been previously reported to suppress those transcripts (44,45).…”

Section: Discussionmentioning

confidence: 99%

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CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 and Has a Therapeutic Effect on HPV-Induced Neoplasia

Ajiro

Sakai

Onogi³

et al. 2018

Clinical Cancer Research

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Cervical cancer is one of the leading causes of cancer-related deaths among women worldwide. The purpose of this study is to assess the therapeutic effect of the newly developed cyclin-dependent kinase 9 (CDK9) inhibitor FIT-039 on cervical neoplasia induced by human papillomavirus (HPV) infection. We examined FIT-039 for its effect on HPV gene expression in HPV cervical cancer cells. Primary keratinocytes monolayer and organotypic raft culture models were used to evaluate HPV viral replication and cervical intraepithelial neoplasia (CIN) phenotypes. Preclinical pharmacokinetics and toxicity tests for FIT-039 were also conducted. Finally, the anti-HPV effect of FIT-039 was further examined , using HPV cervical cancer xenografts. FIT-039 inhibits HPV replication and expression of E6 and E7 viral oncogenes, restoring tumor suppressors p53 and pRb in HPV cervical cancer cells. The therapeutic effect of FIT-039 was demonstrated in CIN model of an organotypic raft culture, where FIT-039 suppressed HPV18-induced dysplasia/hyperproliferation with reduction in viral load. FIT-039 also repressed growth of HPV16, but not HPV cervical cancer xenografts without any significant adverse effects. Safety and pharmacokinetics of FIT-039 were confirmed for systemic and topical routes. The CDK9 inhibitor FIT-039 showed potent anti-HPV activity without significant toxicity in preclinical studies. Thus, FIT-039 is expected to be a novel therapeutic for CIN to prevent cervical cancer. .

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 and Has a Therapeutic Effect on HPV-Induced Neoplasia

Ajiro

Sakai

Onogi³

et al. 2018

Clinical Cancer Research

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“…The HSV-1 gB gene copy number was clearly reduced as shown by qPCR, suggesting that the HCFC1R1 deficiency affects HSV-1 propagation (Figure 6A). To further ask if loss of HCFC1R1 was correlated with the life cycle of HSV-1, we analyzed the mRNA expression of several viral genes including ICP0 (representing immediate early gene), TK (early gene), and GD (late gene) in the control and BGC-823 HCFC1R1−/− cells by qRT-PCR in 24, 48, and 72 hours after infection (25–27). qRT-PCR data showed that missing HCFC1R1 significantly inhibited the mRNA transcription in BGC-823 HCFC1R1−/− cells at the various time points (Figure 6B, C, D).…”

Section: Resultsmentioning

confidence: 99%

HCFC1R1 Deficiency Blocks Herpes Simplex Virus-1 Infection by Inhibiting Nuclear Translocation of HCFC1 and VP16

Shen

Zhao

et al. 2020

Preprint

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Upon HSV-1 infection, viral protein 16 (VP16), supported by Host Cell 21 Factor C1 (HCFC1), is rapidly transported into the nucleus, and help to express a series 22 of HSV-1 immediate-early proteins to begin its lytic replication. However, no direct 23 evidence has shown if the HCFC1 deficiency can affect the proliferation of HSV-1 so far. 24 Here, we showed that the HCFC1 deficiency led to a strong resistance to HSV-1 infection. 25 Moreover, we identified Host Cell Factor C1 Regulator 1 (HCFC1R1) as a new host 26 factor acting early in HSV infection for the transport of the HSV-1 capsid to the nucleus. 27 The HCFC1R1 deficiency also led to a strong resistance to HSV-1 infection. The 28 HCFC1R1 deficiency did not affect the attachment of HSV-1 to host cells but act early in 29 HSV-1 infection by perturbing the formation of HCFC1/VP16 complex. Remarkably, in 30 addition to wild-type HSV-1 infection, the host cells in the absence of either HCFC1 or 31 HCFC1R1 showed strong resistant to the infection of TK-deficient HSV-1, which strain 32 can course severe symptoms and tolerate to the current anti-HSV drug Acyclovir. Our 33 data suggest that HCFC1 or HCFC1R1 may be used as the novel target for developing 34 anti-HSV-1 therapies. 35IMPORTANCE Herpes simplex virus-1 (HSV-1) is widely spread in the human 36 population and can cause a variety of herpetic diseases. Acyclovir, a guanosine analogue 37 that targets the TK protein of HSV-1, is the first specific and selective anti-HSV-1 drug. 38However, the rapid emergence of resistant HSV-1 strains is occurring worldwide, 39 endangering the efficacy of Acyclovir. Alternatively, targeting host factors is another 40 strategy to stop HSV-1 infection. Unfortunately, although the HSV-1's receptor, 41 was discovered in 1998, no effective antiviral drug to date has been developed by 42 targeting Nectin-1. Targeting multiple pathways is the ultimate choice to prevent HSV-1 43 infection. Here we demonstrated that the deletion of HCFC1 or HCFC1R1 exhibits a 44 strong inhibitory effect on both wild-type and TK-deficient HSV-1. Overall, we present 45 evidence that HCFC1 or HCFC1R1 may be used as the novel target for developing 46 anti-HSV-1 therapies with a defined mechanism of action. 47 Key Words: Herpes simplex virus; HCFC1R1; VP16; HCFC1；HSV-1 48 49 50 51 52 53 54 55 3Herpes simplex virus 1 (HSV-1) is a member of the alphaherpesvirus family, which can 56 establish both lytic and latent infection (1, 2). Upon HSV-1 infection, HSV glycoprotein 57 B or C mediates viral adhesion by binding to heparan sulfate proteoglycans on the cell 58 surface, followed by HSV glycoprotein D interacting with Nectin-1, HVEM, and 59 3-O-sulfated heparan sulfate (3-5). For the viral genome that replicates in the nucleus, the 60 viral entry also entails the extensive movement of viruses passing through the cytoplasm. 61In this context, the capsid of HSV-1 may be transported to the nuclear pore complex 62 (NPC) through a vascular bundle since electronic microscopy analysis has shown 63 ne...

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“…Cyclin T1 (CCNT1) is a regulatory subunit of the CDK9/cyclin-T1 cyclin-dependent kinase complex, which promotes transcription via phosphorylation of RNA polymera-se II [64]. This complex is a target of many anti-cancer drugs [65][66][67] and is important for anti-viral therapy as well [68][69][70].…”

Section: Resultsmentioning

confidence: 99%

Untitled

2017

Biopolym. Cell

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To identify novel protein partners of translation factor eEF1Bβ in nucleus of human lung carcinoma cells. Methods. Protein partners of eEF1Bβ in the nuclear fraction of A549 cells were identified by co-immunoprecipitation (co-IP) combined with liquid chromatographytandem mass spectrometry (LC-MS/MS). Specific protein partners of eEF1Bβ were further selected by using the results of previously published global, quantitative and dynamic mapping of protein subcellular localization with help of "Mapofthecell" program. Results. 104 highscored proteins interacting with eEF1Bβ in the nuclear fraction of A549 cells have been identified by mass-spectrometry. Among these proteins, 9 partners of eEF1Bβ were confirmed by the co-fractionation approach. Functional analysis of the partners has divided them on the pro-oncogenic (lung-cancer related) and neutral/anti-oncogenic moieties. These two groups are estimated to be spatially separated in human cancer cells. Conclusions. The position of eEF1Bβ as a link between the oncogenic and neutral/tumor-suppressor moieties of its protein partners in nucleus of lung cancer cells is suggested. Deciphering of a possible role of the eEF1Bβ distribution between the pro-cancer or anti-cancer communities of its protein partners can be a subject of further research.

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CDK9 and SPT5 proteins are specifically required for expression of herpes simplex virus 1 replication-dependent late genes

Cited by 14 publications

References 58 publications

CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 and Has a Therapeutic Effect on HPV-Induced Neoplasia

CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 and Has a Therapeutic Effect on HPV-Induced Neoplasia

HCFC1R1 Deficiency Blocks Herpes Simplex Virus-1 Infection by Inhibiting Nuclear Translocation of HCFC1 and VP16

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