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Biomedical subjects

Andrei L Gartel

Publications and source records attributed to Andrei L Gartel.

16 recordsLinked to original sources
PubMed2006

Identification of a chemical inhibitor of the oncogenic transcription factor forkhead box M1.

The oncogenic transcription factor forkhead box M1 (FoxM1) is overexpressed in a number of different carcinomas, whereas its expression is turned off in terminally differentiated cells. For this reason, FoxM1 is an attractive target for therapeutic intervention in cancer treatment. As a first step toward realizing this goal, in this study, using a high-throughput, cell-based assay system, we screened for and isolated the antibiotic thiazole compound Siomycin A as an inhibitor of FoxM1. Interestingly, we observed that Siomycin A was able to down-regulate the transcriptional activity as well as the protein and mRNA abundance of FoxM1. Consequently, we found that the downstream target genes of FoxM1, such as Cdc25B, Survivin, and CENPB, were repressed. Also, we observed that consistent with earlier reports of FoxM1 inhibition, Siomycin A was able to reduce anchorage-independent growth of cells in soft agar. Furthermore, we found that Siomycin A was able to induce apoptosis selectively in transformed but not normal cells of the same origin. Taken together, our data suggest that FoxM1 inhibitor Siomycin A could represent a useful starting point for the development of anticancer therapeutics.

Animals↗
PubMed2006

A novel transcriptional inhibitor induces apoptosis in tumor cells and exhibits antiangiogenic activity.

Using a high-throughput cell-based assay, we identified a nucleoside analogue 4-amino-6-hydrazino-7-beta-D-ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide (ARC), which has the properties of a general transcriptional inhibitor. Specifically, ARC inhibits the phosphorylation of RNA polymerase II by positive transcription elongation factor-b, leading to a block in transcriptional elongation. ARC was able to potently repress p53 targets p21 and hdm2 (human homologue of mdm2) protein levels, but dramatically increased p53 levels similar to other transcriptional inhibitors, including flavopiridol. This increase in p53 corresponded to the down-regulation of short-lived protein hdm2, which is a well-established negative regulator of p53. Remarkably, ARC induced potent apoptosis in human tumor and transformed, but not in normal cells, and possessed strong antiangiogenic activity in vitro. Although ARC promoted the accumulation of p53, ARC-induced apoptosis in tumor cells was p53-independent, suggesting that it may be useful for the treatment of tumors with functionally inactive p53. Furthermore, cell death induced by ARC had a strong correlation with down-regulation of the antiapoptotic gene survivin, which is often overexpressed in human tumors. Taken together, our data suggests that ARC may be an attractive candidate for anticancer drug development.

Angiogenesis Inhibitors↗
PubMed2006

CDK9 phosphorylates p53 on serine residues 33, 315 and 392.

Tumor suppressor p53 is often activated in response to DNA damage or other forms of stress, leading to either cell cycle arrest or apoptosis. Stress-induced kinases phosphorylate p53 thereby enhancing its stability, leading to an increase in transactivation of its target genes. Several different protein kinases phosphorylate p53 on multiple amino acid residues. Here, we report for the first time that Cyclin dependent kinase 9, whose well-known substrate is RNA polymerase II, can also phosphorylate p53. Specifically, Ser33 on the N-terminus and, Ser315 and Ser392 on the C-terminus of p53 were found to be phosphorylated. The precise biological role of this phosphorylation remains to be elucidated.

Amino Acid Sequence↗
PubMed2006

RNA interference in cancer.

In the recent years, RNA interference (RNAi) has emerged as a major regulatory mechanism in eukaryotic gene expression. The realization that changes in the levels of microRNAs are directly associated with cancer led to the recognition of a new class of tumor suppressors and oncogenes. Moreover, RNAi has been turned into a potent tool for artificially modulating gene expression through the introduction of short interfering RNAs. A plethora of individual inhibitory RNAs as well as several large collections of these reagents have been generated. The systems for stable and regulated expression of these molecules emerged as well. These tools have helped to delineate the roles of various cellular factors in oncogenesis and tumor suppression and laid the foundation for new approaches in gene discovery. Furthermore, successful inhibition of tumor cell growth by RNAi aimed at oncogenes in vitro and in vivo supports the enthusiasm for potential therapeutic applications of this technique. In this article we review the evidence of microRNA involvement in cancer, the use of short interfering RNAs in forward and reverse genetics of this disease, and as well as both the benefits and limitations of experimental RNAi.

Animals↗
PubMed2005

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

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.

Animals↗
PubMed2005

The PPAR-gamma agonist pioglitazone post-transcriptionally induces p21 in PC3 prostate cancer but not in other cell lines.

The anti-diabetic thiozolidinedione compound pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, has been found to have growth inhibitory effects in some cancer cells. The mechanism underlying this growth suppression is not well understood. In this study, we evaluated the effect of pioglitazone on p53 and p21 expression in various cancer cell lines with different p53 status. The cells with wild type p53 did not show any change in p53 levels in response to pioglitazone. Also, none of the cell lines exhibited p53-dependent or independent transcriptional induction of p21(WAF1/CIP1) by pioglitazone. However, PC3, an androgen-insensitive prostate cancer cell line with deletion of p53 showed an appreciable post-transcriptional induction of p21 expression after treatment with pioglitazone. These results imply that pioglitazone generally does not modulate p21 transcription in human cancer cell lines.

Cell Line, Tumor↗
PubMed2004

A novel p21WAF1/CIP1 transcript is highly dependent on p53 for its basal expression in mouse tissues.

p21WAF1/CIP1 is an important transcriptional target of p53 and it plays a critical role in growth arrest after DNA damage. Here, we report the identification of a novel alternate mouse p21 transcript that is conserved in evolution. It differs from the classical p21WAF1/CIP1 transcript in the first exon, which is located at approximately 2.8 kb upstream of transcriptional start site of p21WAF1/CIP1 and is sandwiched between two p53 binding sites. This novel p21 transcript is present in most mouse tissues with highest levels of expression in the spleen. In contrast to the classical p21WAF1/CIP1 transcript, this new transcript is highly dependent on p53 for its basal expression, as evidenced by its absence in nearly all of p53-/- mouse tissues. This transcript is also absent at nonpermissive temperature in a 10-1 mouse cell line lacking endogenous p53 and harboring temperature-sensitive p53 mutant. However, this novel transcript is induced to appreciable levels in the presence of high p53 activity at the permissive temperature. Our data suggest that p53-dependent induction of p21 may be an additive effect conferred by individual increases in the alternate and classical p21 transcripts.

Animals↗
PubMed2004

Myc-ARF (alternate reading frame) interaction inhibits the functions of Myc.

The tumor suppressor protein ARF (alternate reading frame) inhibits MDM2 to stabilize and activate the functions of p53. Here we provide evidence for an additional activity of ARF that attenuates cell cycle progression independently of p53 activation. We show that ARF interacts with c-Myc independently of MDM2 or p53. Consequently, ARF relocalizes c-Myc from the nucleoplasm to the nucleolus. Binding and relocalization by ARF correlate with an inhibition of the c-Myc-activated transcription in both p53-positive and -negative cells. Using inducible cell lines, we show that the wild type ARF, but not a mutant, inhibits expression of the c-Myc-induced genes before inhibiting S phase. Moreover, ARF inhibits Myc-induced progression into S phase in cells lacking p53 or expressing a defective p53, indicating that ARF inhibits the S phase stimulatory function of c-Myc independently of p53. Our results strongly suggest that cMyc is a bona fide target of ARF and that ARF attenuates c-Myc independently of the ARF-p53 axis.

Alternative Splicing↗
PubMed2004

RNA interference as a new strategy against viral hepatitis.

Hepatitis viruses are the leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. Since currently available treatment options against these viruses are limited, there is a need for development of alternative therapies. In this minireview, we concentrate on three hepatitis viruses--hepatitis C virus, hepatitis B virus, and hepatitis delta virus and discuss how RNA interference (RNAi) has been utilized against them. RNAi is a process by which small double-stranded RNA can effectively target a homologous RNA sequence for degradation by cellular ribonucleases. Though RNAi was exploited in the beginning for down-regulating cellular genes, it has recently been demonstrated that this process is equally effective against many types of human and animal viruses including the hepatitis viruses. Both synthetic small-interfering RNAs (siRNAs) and plasmid-based siRNA expression systems have been useful in suppressing the hepatitis viruses. Though this new approach looks promising, problems of nonspecific effects and delivery may need to be addressed before the full therapeutic potential of RNAi against viral infections in patients is realized.

Animals↗
PubMed2004

Constitutive expression of E2F-1 leads to p21-dependent cell cycle arrest in S phase of the cell cycle.

p21 is a potent inhibitor of cyclin-dependent kinases capable of arresting cell cycle progression. p21 is primarily regulated at the transcriptional level by several transcription factors, including p53. Previously, we reported that certain members of the E2F family of transcription factors may activate p21 transcription via a p53-independent mechanism. To further elucidate the consequences of E2F-1-regulated induction of p21, we developed cell lines with a tamoxifen-dependent form of E2F-1. We confirmed direct interaction of E2F-1 with the proximal region of the p21 promoter. Interestingly, elevated E2F-1 activity was sufficient to arrest a substantial subset of cells in S phase and this effect was correlated to and dependent on the induction of p21 protein. Since E2F proteins control genes required for cell cycle progression and are activated by various oncogenic events, we believe that the p21-dependent arrest described in this report represents an additional mechanism that guards against unrestricted cell proliferation.

Animals↗
PubMed2003

Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes.

Constitutive expression of the proto-oncogene c-myc results in oncogenic activation and contributes to progression of a wide range of human and animal tumors. Myc executes its multiple activities mostly through transcriptional regulation of the target genes. The special interest of this review is the mechanism of transcriptional repression of cell cycle inhibitors by Myc. Myc suppresses expression of cell cycle/growth arrest genes gas1, p15, p21, p27, and gadd34, -45, and -153. It appears that Myc represses growth arrest gene transcription by at least two distinct mechanisms. One mechanism is limited to the binding of Myc-Max heterodimers to the Inr element in their promoters and inhibition of Miz-1 or other transcriptional activators via the C-terminal domain of c-Myc. This mechanism requires DNA binding of the Myc-Max complex to Inr sequences. The other mechanism is dependent on c-Myc binding to the Sp1 transcription factor via the c-Myc central region and inhibition of Sp1 transcriptional activity. At this time it is not entirely clear which Sp1-containing promoters will be repressed by c-Myc and what other modes of c-Myc transcriptional repression may exist. The ability of c-Myc to repress transcription of growth arrest genes may contribute to its potential to promote proliferation and oncogenesis.

Animals↗
PubMed2003

A new method for determining the status of p53 in tumor cell lines of different origin.

The tumor suppressor p53 is the most frequently mutated gene in human tumors. In response to DNA damage, aberrant growth signals, or chemotherapeutic drugs, p53 is stabilized and induces apoptosis and/or cell cycle arrest. While the mechanisms of p53-dependent apoptosis are not well understood, p53-dependent cycle arrest is primary mediated by the CDK inhibitor p21. p53 is a transcriptional activator and it is not surprising that a majority of p53 mutations occur in the core DNA binding domain and affect DNA binding and transactivation of p53 targets in tumors. We used the capability of p53 to activate transcription for developing a new assay that permits rapid determination of the status of p53 in cancer cell lines of different origin. Our strategy involved using a retrovirus containing a p53-regulated lacZ reporter gene that was introduced into colon and breast tumor cell lines to determine p53 status. Simple staining for beta-galactosidase allowed us to confirm that the colon cancer cell lines LIM1215 and HCT116, as well as the breast cancer cell line MCF7. have wild-type p53, and the colon cancer cell line Caco-2 as well as breast cancer cell lines MDA-MB-435 and MDA-MB-231 have mutant p53. This method may be applied to novel cell lines of any origin with unknown status of p53.

Biological Assay↗
PubMed2002

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

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.

Animals↗