Cancer develops when the balance between cell proliferation and cell death is disrupted, and the ensuing aberrant proliferation leads to tumor growth. The cyclin-dependent kinase inhibitor p21 is induced by both p53-dependent and -independent mechanisms following stress, and induction of p21 may cause cell cycle arrest. As a proliferation inhibitor, p21 is poised to play an important role in preventing tumor development. This notion is supported by data indicating that p21-null mice are more prone to spontaneous and induced tumorigenesis, and p21 synergizes with other tumor suppressors to protect against tumor progression in mice. However, a number of recent studies have pointed out that in addition to being an inhibitor of cell proliferation, p21 acts as an inhibitor of apoptosis in a number of systems, and this may counteract its tumor-suppressive functions as a growth inhibitor. In the current review, we discuss the role of p21 in regulating cell death and the potential relevance of its expression in cancer.

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The role of the cyclin-dependent kinase inhibitor p21 in apoptosis.

The cyclin-dependent kinase inhibitor p21WAF1/CIP1 is a major player in cell cycle control and it is mainly regulated at the transcriptional level. Whereas induction of p21 predominantly leads to cell cycle arrest, repression of p21 may have a variety of outcomes depending on the context. In this review, we concentrate on transcriptional repression of p21 by cellular and viral factors, and delve in detail into its possible biological implications and its role in cancer. It seems that the major mode of p21 transcriptional repression by negative regulators is the interference with positive transcription factors without direct binding to the p21 promoter. Specifically, the negative factors may either inhibit binding of positive regulators to the promoter or hinder their transcriptional activity. The ability of p21 to inhibit proliferation may contribute to its tumor suppressor function. Because of this, it is not surprising that a number of oncogenes repress p21 to promote cell growth and tumorigenesis. However, p21 is also an inhibitor of apoptosis and p21 repression may also have an anticancer effect. For example, c-Myc and chemical p21 inhibitors, which repress p21, sensitize tumor cells to apoptosis by anticancer drugs. Further identification of factors that repress p21 is likely to contribute to the better understanding of its role in cancer.

https://cancerres.aacrjournals.org/content/canres/65/10/3980.full.pdf

Lost in transcription: p21 repression, mechanisms, and consequences.

https://zenodo.org/record/1259447/files/article.pdf

Evolutionary genomics of Nucleo-Cytoplasmic Large DNA Viruses

Triptolide (1) is a structurally unique diterpene triepoxide isolated from a traditional Chinese medicinal plant with anti-inflammatory, immunosuppressive, contraceptive and antitumor activities. Its molecular mechanism of action, however, has remained largely elusive to date. We report that triptolide covalently binds to human XPB (also known as ERCC3), a subunit of the transcription factor TFIIH, and inhibits its DNA-dependent ATPase activity, which leads to the inhibition of RNA polymerase II-mediated transcription and likely nucleotide excision repair. The identification of XPB as the target of triptolide accounts for the majority of the known biological activities of triptolide. These findings also suggest that triptolide can serve as a new molecular probe for studying transcription and, potentially, as a new type of anticancer agent through inhibition of the ATPase activity of XPB.

/pdf/xpb-a-subunit-of-tfiih-is-a-target-of-the-natural-product-1rl03twcml.pdf

XPB, a subunit of TFIIH, is a target of the natural product triptolide

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae).

Triptolide and chemotherapy cooperate in tumor cell apoptosis. A role for the p53 pathway.

The Poxvirus p28 Virulence Factor Is an E3 Ubiquitin Ligase

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2899%2901283-1

Loss of STAT1 expression confers resistance to IFN-γ-induced apoptosis in ME180 cells

Hepatitis C virus (HCV) infection is one of the major causes of viral hepatitis, with a great propensity to induce chronicity (21). Liver inflammation can persist for decades in chronic HCV infection and eventually leads to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. HCV infection is a significant health care problem: it is estimated that approximately 170 million individuals are chronically infected with HCV worldwide, with ∼30,000 cases of new infection each year in the United States alone (1, 2, 46). No vaccine is currently available to prevent HCV infection. The standard treatment for HCV infection, a combination of pegylated alpha interferon (IFN-α) and ribavirin (RBV), is limited by its suboptimal response rate in a significant patient population, side effects, and affordability (11). Thus, it is critical to discover highly effective, safer therapies to improve the clinical management of HCV infection.

HCV is an enveloped RNA virus belonging to the family Flaviviridae (9). HCV clinical isolates display high heterogeneity in their genomic RNA and amino acid sequences, and they are classified into six genotypes and numerous subtypes (49). It is documented that infections by different genotypes may produce different clinical outcomes and may respond differently to IFN-α-based antiviral treatment (for a review, see reference 11). Significantly, patients infected with genotype 1 viruses, which account for approximately 70% of HCV infections in the United States, exhibit poor rates of response to the IFN-α-based treatment. An ideal antiviral should, therefore, be effective against the majority, if not all, of the HCV genotypes.

Upon entering the host cell, HCV releases its 9.6-kb genomic RNA into the cytoplasm, where it directs the translation of a single polyprotein of about 3,000 amino acids. The giant polyprotein is cotranslationally processed by host and viral proteases into structural proteins (core, E1, and E2) and nonstructural proteins (P7, NS2, NS3, NS4a, NS4b, NS5a, and NS5b). The mature nonstructural proteins (except P7 and NS2) and host factors assemble into membrane-associated RNA replication complexes, where a vast quantity of progeny viral RNA molecules are amplified from the incoming HCV genomic RNA (14, 18, 35). Although all the steps in the HCV life cycle can be targeted for drug discovery against HCV, the viral nonstructural proteins, specifically NS3 and NS5b, which encode well-defined enzymatic activities crucial for viral replication, are the major targets for antiviral discovery (10, 53). However, the replication of HCV viral RNA by the viral replication complex is quickly becoming another focus for drug discovery with the development of the HCV replicon system.

Until the establishment of HCV replicons, the analysis of HCV replication was hampered due to the lack of a robust HCV cell culture system (5, 38). The first-generation HCV replicons are human hepatoma Huh-7 cell lines carrying engineered genotype 1b subgenomic RNA with the following genome organization: HCV 5′ nontranslated region (5′ NTR)-neomycin phosphotransferase (NPT) gene (also referred to as the neomycin resistance [Neor] gene)-encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES)-HCV NS3-4a-4b-5a-5b-HCV 3′ NTR. Subsequent studies have shown that the efficiency of replicon establishment can be enhanced substantially by incorporating cell culture-adaptive mutations, especially those in NS3 and NS5a (5, 26, 37, 38). The HCV replicon system has been an effective tool for studying viral RNA replication and virus-host interactions. It also serves as an important cell-based system with which to evaluate antiviral drugs and to reveal drug resistance mechanisms (for a review, see reference 4). Moreover, the HCV replicon presents a unique drug-screening system, allowing for the screening of compounds inhibiting the viral enzymes as well as other targets of the HCV RNA replication process in a cellular environment. Such screens would perhaps facilitate the discovery of inhibitors that block the functions of NS4b and NS5a or interrupt virus-host interactions, discoveries that cannot be readily achieved with biochemical screens. Several efforts have already been made to screen small-molecule compound libraries against different versions of the HCV replicon system (17, 47, 50, 55). Here we describe the development of an HCV replicon assay for high-throughput screening and the characterization of one of the heterocyclic hits from screens of a 230,000-member chemical library. We show that the lead compound of this hit scaffold is effective at inhibiting HCV replicons of different genotypes and can enhance the inhibitory activity of IFN-α in the replicon model.

Emily Anderson

Papers

Triptolide and chemotherapy cooperate in tumor cell apoptosis. A role for the p53 pathway.

The Poxvirus p28 Virulence Factor Is an E3 Ubiquitin Ligase

Loss of STAT1 expression confers resistance to IFN-γ-induced apoptosis in ME180 cells

Discovery and Characterization of Substituted Diphenyl Heterocyclic Compounds as Potent and Selective Inhibitors of Hepatitis C Virus Replication