Transcription factors LSF and E2Fs: Tandem cyclists driving G0 to S?

Hansen, Ulla; Owens, Laura; Saxena, Utsav

doi:10.4161/cc.8.14.9089

Cited by 31 publications

(31 citation statements)

References 45 publications

(65 reference statements)

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“…Although there is no known protein structure for members of the LSF transcription factor family, and no apparent protein sequence homology outside of this small family to the LSF DNA-binding region (19), one report used a variety of protein-folding algorithms to predict that the DNA-binding region is similar in structure to that of the p53 transcription factor family (20). Our structure-function analyses of LSF DNA binding are consistent with this prediction (13). Thus, we tested whether p53-mediated transcription would be influenced by FQI1 treatment.…”

Section: Resultssupporting

confidence: 65%

“…LSF, a member of a small family of transcription factors conserved throughout the animal kingdom (11), is ubiquitously expressed in mammalian tissues and cell lines (12). LSF activity is tightly controlled as cells progress from quiescence into DNA replication (G0 to S) (13,14), and is required for efficient progression of cells through the G1/S transition (15,16). Regulation of LSF activity normally occurs via posttranslational modifications, with LSF protein levels generally being low and constant.…”

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confidence: 99%

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Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma

Grant¹,

Bishop

Christadore

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Despite the prevalence of HCC, there is no effective, systemic treatment. The transcription factor LSF is a promising protein target for chemotherapy; it is highly expressed in HCC patient samples and cell lines, and promotes oncogenesis in rodent xenograft models of HCC. Here, we identify small molecules that effectively inhibit LSF cellular activity. The lead compound, factor quinolinone inhibitor 1 (FQI1), inhibits LSF DNA-binding activity both in vitro, as determined by electrophoretic mobility shift assays, and in cells, as determined by ChIP. Consistent with such inhibition, FQI1 eliminates transcriptional stimulation of LSF-dependent reporter constructs. FQI1 also exhibits antiproliferative activity in multiple cell lines. In LSF-overexpressing cells, including HCC cells, cell death is rapidly induced; however, primary or immortalized hepatocytes are unaffected by treatment with FQI1. The highly concordant structure–activity relationship of a panel of 23 quinolinones strongly suggests that the growth inhibitory activity is due to a single biological target or family. Coupled with the striking agreement between the concentrations required for antiproliferative activity (GI 50 s) and for inhibition of LSF transactivation (IC 50 s), we conclude that LSF is the specific biological target of FQIs. Based on these in vitro results, we tested the efficacy of FQI1 in inhibiting HCC tumor growth in a mouse xenograft model. As a single agent, tumor growth was dramatically inhibited with no observable general tissue cytotoxicity. These findings support the further development of LSF inhibitors for cancer chemotherapy.

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Section: Resultssupporting

confidence: 65%

mentioning

confidence: 99%

Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma

Grant¹,

Bishop

Christadore

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Our recent studies reveal that astrocyte elevated gene-1 (AEG-1) is overexpressed in >90% of human HCC patients, compared to normal liver, and AEG-1 plays a key role in regulating development and progression of HCC (5). The transcription factor Late SV40 Factor (LSF) was identified as a downstream gene of AEG-1, and we demonstrated that LSF mediates, in part, AEG-1-induced resistance to 5-fluorouracil (5-FU) in HCC cells (5, 6).LSF, also known as LBP-1c and TFCP2, regulates diverse cellular and viral promoters (7,8). A major cellular target of LSF is the thymidylate synthase (TS) gene, which encodes the ratelimiting enzyme in the production of dTTP, required for DNA synthesis (9).…”

mentioning

confidence: 99%

“…LSF, also known as LBP-1c and TFCP2, regulates diverse cellular and viral promoters (7,8). A major cellular target of LSF is the thymidylate synthase (TS) gene, which encodes the ratelimiting enzyme in the production of dTTP, required for DNA synthesis (9).…”

mentioning

confidence: 99%

Transcription factor Late SV40 Factor (LSF) functions as an oncogene in hepatocellular carcinoma

Yoo¹,

Emdad

Gredler³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Hepatocellular carcinoma (HCC) is a highly aggressive cancer with no currently available effective treatment. Understanding of the molecular mechanism of HCC development and progression is imperative for developing novel, effective, and targeted therapies for this lethal disease. In this article, we document that the cellular transcription factor Late SV40 Factor (LSF) plays an important role in HCC pathogenesis. LSF protein was significantly overexpressed in human HCC cells compared to normal hepatocytes. In 109 HCC patients, LSF protein was overexpressed in >90% cases, compared to normal liver, and LSF expression level showed significant correlation with the stages and grades of the disease. Forced overexpression of LSF in less aggressive HCC cells resulted in highly aggressive, angiogenic, and multiorgan metastatic tumors in nude mice. Conversely, inhibition of LSF significantly abrogated growth and metastasis of highly aggressive HCC cells in nude mice. Microarray studies revealed that as a transcription factor, LSF modulated specific genes regulating invasion, angiogenesis, chemoresistance, and senescence. The expression of osteopontin (OPN), a gene regulating every step in tumor progression and metastasis, was robustly up-regulated by LSF. It was documented that LSF transcriptionally up-regulates OPN, and loss-of-function studies demonstrated that OPN plays an important role in mediating the oncogenic functions of LSF. Together, these data establish a regulatory role of LSF in cancer, particularly HCC pathogenesis, and validate LSF as a viable target for therapeutic intervention.metastasis | osteopontin | transcription regulation H epatocellular carcinoma (HCC) is one of the five most common cancers worldwide (1). The incidence of HCC is increasing despite a decrease in overall incidence of all cancers (2, 3). In the United States, the estimated new cases of HCC for 2008 were 21,370, of which 18,410 were expected to die (2). The mortality rate of HCC parallels that of its incidence because HCC is a tumor with rapid growth and early vascular invasion that is resistant to conventional chemotherapy, and no systemic therapy is available for the advanced disease (4). As such, understanding the molecular mechanism of HCC development and progression is imperative to establish novel, effective, and targeted therapies for this highly aggressive cancer. Our recent studies reveal that astrocyte elevated gene-1 (AEG-1) is overexpressed in >90% of human HCC patients, compared to normal liver, and AEG-1 plays a key role in regulating development and progression of HCC (5). The transcription factor Late SV40 Factor (LSF) was identified as a downstream gene of AEG-1, and we demonstrated that LSF mediates, in part, AEG-1-induced resistance to 5-fluorouracil (5-FU) in HCC cells (5, 6).LSF, also known as LBP-1c and TFCP2, regulates diverse cellular and viral promoters (7,8). A major cellular target of LSF is the thymidylate synthase (TS) gene, which encodes the ratelimiting enzyme in the production of dTTP, required for DNA ...

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“…Saxena és munkatársai megállapították, hogy NIH 3T3 egér fibroblasztok korai G1 fázisában a CCNC kötődhet a CDK2 (ciklin-dependens kináz 2) enzimhez is, mivel ahogyan egyes laboratóriumi egér törzsekből, így ezekből a sejtekből is hiányzik a CDK3 (17,18). Ez a komplex foszforilálja az LSF (late Simian virus 40 factor) transzkripciós faktort a 309. szerinnél (17,19). Az S309 foszforiláció meggátolja azt, hogy az LSF még a G1 fázisban indukáljon olyan, jellemzően S-fázis géneket, mint például a timidin bioszintézisében kulcsszerepet játszó Tyms (timidilát szintáz).…”

Section: Sejtbiológiai Szerepekunclassified

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Transcription factors LSF and E2Fs: Tandem cyclists driving G0 to S?

Cited by 31 publications

References 45 publications

Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma

Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma

Transcription factor Late SV40 Factor (LSF) functions as an oncogene in hepatocellular carcinoma

A ciklin C promóter működésének jellegzetességei emlősökben

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