Securin Is Required for Chromosomal Stability in Human Cells

Jallepalli, Prasad V.; Waizenegger, Irene C.; Bunz, Fred; Langer, Sabine; Speicher, Michael R.; Peters, Jan‐Michael; Kinzler, Kenneth W.; Vogelstein, Bert; Lengauer, Christoph

doi:10.1016/s0092-8674(01)00340-3

Cited by 358 publications

(344 citation statements)

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“…The KO-2 construct represented a bipartite targeting vector system with an additional recombination site designed into the middle portion of the neomycin resistance gene 37 . Transfection, selection and PCR screening strategies for somatic-cell homologous recombination have been described 22 .…”

Section: Targeted Disruption Of Fdxr By Homologous Recombinationmentioning

confidence: 99%

Ferredoxin reductase affects p53-dependent, 5-fluorouracil–induced apoptosis in colorectal cancer cells

Hwang

Bunz

et al. 2001

Nat Med

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Loss of p53 gene function, which occurs in most colon cancer cells, has been shown to abolish the apoptotic response to 5-fluorouracil (5-FU). To identify genes downstream of p53 that might mediate these effects, we assessed global patterns of gene expression following 5-FU treatment of isogenic cells differing only in their p53 status. The gene encoding mitochondrial ferredoxin reductase (protein, FR; gene, FDXR) was one of the few genes significantly induced by p53 after 5-FU treatment. The FR protein was localized to mitochondria and suppressed the growth of colon cancer cells when over-expressed. Targeted disruption of the FDXR gene in human colon cancer cells showed that it was essential for viability, and partial disruption of the gene resulted in decreased sensitivity to 5-FU-induced apoptosis. These data, coupled with the effects of pharmacologic inhibitors of reactive oxygen species, indicate that FR contributes to p53-mediated apoptosis through the generation of oxidative stress in mitochondria.5-fluorouracil (5-FU) has been in clinical use for several decades and is still the most effective adjuvant therapy for patients with colon cancer. Metabolically, it acts by blocking the enzyme thymidylate synthase and by inhibiting both RNA and DNA synthesis. Like most chemotherapeutic agents, 5-FU induces marked apoptosis in sensitive cells. However, the molecular mechanisms underlying this apoptosis are only beginning to be elucidated.Several studies have suggested a correlation between inactivation of p53 and resistance to 5-FU, both in patients and in experimental systems 1,2 . For example, a profound resistance to 5-FU-induced apoptosis was observed in a human colon cancer cell line with a targeted disruption of the p53 gene (Trp53) 3 . Such observations support a genetic basis for 5-FU chemosensitivity and indicate that isogenic cells differing only in p53 status represent a useful system for studying chemosensitivity in vitro.© 2001 Nature Publishing Group Correspondence should be addressed to B.V.; vogelbe@welch.jhu.edu. Supplementary information is available on the Nature Medicine website (http://medicine.nature.com/supplementary_info/). NIH Public Access NIH-PA Author ManuscriptThe mechanisms through which p53 induces apoptosis are the focus of much current research [4][5][6][7] . Several studies have implicated mitochondria-derived reactive oxygen species (ROS) in the process [8][9][10][11] . Though pro-apoptotic members of the Bcl-2 family of proteins have been shown to be induced by p53 and affect mitochondrial permeability, the molecular mechanisms responsible for the formation of mitochondrial ROS remain unclear 12,13 .In an effort to gain further insight into this process, we examined global patterns of gene expression using the serial analysis of gene expression (SAGE) approach 14 . We were particularly interested in finding p53-induced genes that encode mitochondrial proteins with the potential to directly stimulate ROS production. Here we identify mammalian ferredoxin reductase (FR) ...

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Section: Targeted Disruption Of Fdxr By Homologous Recombinationmentioning

confidence: 99%

Ferredoxin reductase affects p53-dependent, 5-fluorouracil–induced apoptosis in colorectal cancer cells

Hwang

Bunz

et al. 2001

Nat Med

Self Cite

384

251

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“…14 Aberrant expression of PTTG1 disrupts mitosis and causes aneuploidy and genetic instability. [14][15][16][17] Aneuploidy is a common characteristic of tumors and has also been proposed as a necessary event for tumorigenesis. 18 Nevertheless, viability and mild phenotypes of PTTG1 knockout mice and human cells strongly suggest that PTTG1 may be dispensable for regulation of sister chromatid and other normal cellular processes as well.…”

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Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growthin vitroandin vivo

et al. 2006

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The pituitary tumor transforming (PTTG) gene family comprises PTTG1, 2, and 3. Forced expression of PTTG1 (securin) induces cellular transformation and promotes tumor development in animal models. PTTG1 is overexpressed in various human cancers. However, the expression and pathogenic implications of the PTTG gene family in hepatocellular carcinoma are largely unknown. Gene silencing using short interfering RNA (siRNA) has become an efficient means to study the functions of genes and has been increasingly used for cancer gene therapy approaches. We report that PTTG1, but not PTTG2 and 3, was highly and frequently expressed in liver cancer tissues from patients and highly in SH-J1, SK-Hep1, and Huh-7 hepatoma cell lines. Adenoviral vector encoding siRNA against PTTG1 (Ad.PTTG1-siRNA) depleted PTTG1 specifically and efficiently in SH-J1 hepatoma cells, which resulted in activation of p53 that led to increased p21 expression and induction of apoptosis. The depletion of PTTG1 in HCT116 colorectal cancer cells exhibited a cytotoxic effect in a p53-dependent manner. Ad.PTTG1-siRNA-mediated cytotoxic effect was dependent on expression levels of PTTG1 and p53 in hepatoma cell lines. Huh-7 hepatoma cells, once transduced with Ad.PTTG1-siRNA, displayed markedly attenuated growth potential in nude mice. Intra-tumor delivery of Ad.PTTG1-siRNA led to significant inhibition of tumor growth in SH-J1 tumor xenograft established in nude mice. In conclusion, PTTG1 overexpressed in hepatoma cell lines negatively regulates the ability of p53 to induce apoptosis. PTTG1 gene silencing using siRNA may be an effective modality to treat liver cancer, in which PTTG1 is abundantly expressed. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/ suppmat/index.html).

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“…PTTG is a securin protein, which regulates chromatid separation during mitosis. 7 Securin overexpression leads to aneuploidy, 8,9 causes in vitro transformation, and tumor formation in vivo, regulates bFGF secretion and induces angiogenesis. 10,11 Securin is expressed at low levels in normal tissues, but is abundantly expressed in human pituitary, 12 thyroid 13 and colorectal tumors, 14 where highest securin mRNA expression was observed in invasive and metastatic cancers.…”

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confidence: 99%

Securin is overexpressed in breast cancer

et al. 2005

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Securin regulates sister chromatid separation during mitosis, induces bFGF-mediated angiogenesis, and securin overexpression causes in vitro transformation and in vivo tumor formation in nude mice. As estrogen administration to oophorectomized rats increased pituitary securin expression, we used immunohistochemistry to examine securin and estrogen receptor alpha (ER-a) expression in 90 breast tumors and 18 normal breast tissues. Breast tumor securin and ER-a expression were quantitated by image analysis and expressed as fold difference relative to securin expression in normal breast tissue. Low cytoplasmic securin expression was seen in the normal breast epithelium, whereas abundant cytoplasmic and nuclear securin expression was demonstrated in all 90 breast tumors. Highest securin expression was seen in brain metastatic breast tumors (4.3-fold, Po0.01), cells derived from metastatic breast cancers (6.5-fold, Po0.001), and in invasive ductal carcinoma (mean7s.e.: 3.8-fold, Po0.001). Highly pleomorphic (4.1-fold) or highly proliferative breast tumors (1.6-fold) exhibited high immunohistochemical securin expression compared to low-grade breast tumors (Po0.05). Northern blot analysis in 12 of the breast tumors confirmed the immunohistochemical findings demonstrating increased securin mRNA expression compared to normal breast mucosa (2.5-fold, P ¼ 0.03), with highest securin evident in invasive (3.5-fold) vs noninvasive tumors (1.9-fold, P ¼ 0.03). In addition, some tumors that exhibited high securin expression also expressed high ER-a levels (Po0.0001). These results demonstrate that the estrogen-induced transforming gene, securin is abundantly expressed in breast carcinoma, and is associated with the presence of metastatic spread, and lymph node invasion. We propose immunohistochemical tumor securin expression as a potential invasive marker, and novel therapeutic target in breast cancer. Modern Pathology (2005) 18, 985-990.

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Securin Is Required for Chromosomal Stability in Human Cells

Cited by 358 publications

References 51 publications

Ferredoxin reductase affects p53-dependent, 5-fluorouracil–induced apoptosis in colorectal cancer cells

Ferredoxin reductase affects p53-dependent, 5-fluorouracil–induced apoptosis in colorectal cancer cells

Adenovirus-mediated transfer of siRNA against PTTG1 inhibits liver cancer cell growthin vitroandin vivo

Securin is overexpressed in breast cancer

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