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Aberrant transcriptional repression through chromatin remodeling and histone deacetylation has been postulated as the driving force for tumorigenesis. FBI-1 (formerly called Pokemon) is a member of the POK family of transcriptional repressors. Recently, FBI-1 was characterized as a critical oncogenic factor that specifically represses transcription of the tumor suppressor gene ARF, potentially leading indirectly to p53 inactivation. Our investigations on transcriptional repression of the p53 pathway revealed that FBI-1 represses transcription of ARF, Hdm2 (human analogue of mouse double minute oncogene), and p21CIP1 (hereafter indicated as p21) but not of p53. FBI-1 showed a more potent repressive effect on p21 than on p53. Our data suggested that FBI-1 is a master controller of the ARF-Hdm2-p53-p21 pathway, ultimately impinging on cell cycle arrest factor p21, by inhibiting upstream regulators at the transcriptional and protein levels. FBI-1 acted as a competitive transcriptional repressor of p53 and Sp1 and was shown to bind the proximal Sp1-3 GC-box and the distal p53-responsive elements of p21. Repression involved direct binding competition of FBI-1 with Sp1 and p53. FBI-1 also interacted with corepressors, such as mSin3A, NCoR, and SMRT, thereby deacetylating Ac-H3 and Ac-H4 histones at the promoter. FBI-1 caused cellular transformation, promoted cell cycle proliferation, and significantly increased the number of cells in S phase. FBI-1 is aberrantly overexpressed in many human solid tumors, particularly in adenocarcinomas and squamous carcinomas. The role of FBI-1 as a master controller of the p53 pathway therefore makes it an attractive therapeutic target.The BTB/POZ 2 domain, originally identified in Drosophila melanogaster bric-à-brac, tramtrack, and broad complex transcription regulators, and in pox virus zinc finger proteins (1, 2), is an evolutionarily conserved protein-protein interaction domain. About 1,000 distinct BTB/POZ entries exist in sequence data bases (3, 4). Among 194 human BTB/POZ domain regulatory proteins, about 40 proteins are POK proteins. POK proteins consist of an N-terminal POZ domain and a C-terminal Krüppel-type (C2H2) zinc finger domain. The C-terminal zinc fingers recognize and bind specific DNA sequences, and the POZ domain mediates homo-or heterodimerization and interacts with other proteins, such as corepressors, histone deacetylase, and other transcription factors, to regulate transcription (2-4).BTB/POZ domain regulatory proteins have various cellular regulatory functions. In particular, some of the POK proteins with a BTB/POZ domain and Krüppel-like zinc finger are major determinants in apoptosis (5), development (6, 7), transcription (8 -14), and oncogenesis (8,11,15,16). The oncogenic members of the POK family include promyelocytic leukemia zinc finger (PLZF) (11, 16), BCL-6 (B cell lymphoma-6) (17), and HIC-1 (hypermethylated in cancer) (18). Another interesting, newly identified POK transcription factor with proto-oncogenic activity is FBI-1 (mouse LRF), encoded by t...

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Gene-modified replication-competent adenoviruses (Ads) are emerging as a promising new modality for the treatment of cancer. We have previously shown that E1B 19kDa and E1B 55kDa gene-deleted Ad (Ad-DeltaE1B19/55) exhibits improved tumor-specific replication and cell lysis, leading to an enhanced antitumor effect. In an effort to increase cancer cell selectivity of a replicating adenovirus, we first generated 11 E1A mutant Ads (Ad-E1mt1 to Ad-E1mt11) with deletion or substitution in retinoblastoma (pRb)-binding sites of E1A. Of these, Ad-E1mt7 demonstrated significant improvement in cytopathic effect (CPE) and viral replication in a cancer cell-specific manner. To further enhance the cancer cell specificity of Ad-E1mt7, Ad-DeltaE1Bmt7 was generated, in which both the E1B 19kDa and E1B 55kDa genes were deleted. As assessed in CPE assay and immunoblot analysis for Ad fiber expression, Ad-DeltaE1Bmt7 exerted marked enhancement in cancer cell-specific killing as well as viral replication in comparison with its comparative controls (Ad-E1mt7, Ad-DeltaE1B55). Furthermore, the growth of established human cervical carcinoma in nude mice was significantly suppressed by intratumoral injection of Ad-DeltaE1Bmt7. In summary, we have developed an oncolytic adenovirus with a significantly improved therapeutic profile for cancer treatment.

Hybrid nanoparticles with multi‐functional capabilities of targeted infection, magnetic resonance (MR) imaging, and gene delivery are developed by fusing virus and MnMEIO magnetic nanoparticles. Their successful utilizations for in vitro target‐specific MR imaging and enhanced green fluorescent protein (eGFP) gene delivery into CAR‐positive cells are demonstrated.