Functional Expression of Human p21WAF1/CIP1Gene in Rat Glioma Cells Suppresses Tumor Growthin Vivoand Induces Radiosensitivity

Hsiao, Michael; Tse, Victor; Carmel, Jason B.; Costanzi, Eugenia; Strauss, Bryan E.; Haas, Martin; Silverberg, Gerald D.

doi:10.1006/bbrc.1997.6450

Cited by 41 publications

(14 citation statements)

References 13 publications

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“…Tumor cells are heterogeneous with respect to their sensitivity to therapeutic agents, and the radioresistant phenotype is often correlated with alterations in cell-cycle checkpoints and slowed growth as well as decreased apoptosis (Coleman and Stevenson, 1996;Maity et al, 1997). Radioresistance has been attributed to the expression of several genes, including p53 (Biard et al, 1994), ras (Sklar, 1988), raf-1 (Kasid et al, 1987), bcl-2 (Kitada et al, 1996), p16 (Matsumura et al, 1997), and p21 (Hsiao et al, 1997), but the molecular mechanisms involved are still unclear.…”

Section: Discussionmentioning

confidence: 99%

Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis

et al. 2007

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Radiotherapy is an effective treatment for some esophageal cancers, but the molecular mechanisms of radiosensitivity remain unknown. RUNX3, a novel tumor suppressor of gastric cancer, functions in transforming growth factor (TGF)-b-dependent apoptosis. We obtained paired samples from 62 patients with advanced esophageal cancers diagnosed initially as T3 or T4 with image diagnosis; one sample was obtained from a biopsy before presurgical radiotherapy, and the other was resected in surgical specimens after radiotherapy. RUNX3 was repressed in 67.7% cases of the pretreatment biopsy samples and 96.7% cases of the irradiated, resected samples. The nuclear expression of RUNX3 was associated with radiosensitivity and a better prognosis than cytoplasmic or no RUNX3 expression (Po0.003); cytoplasmic RUNX3 expression was strictly associated with radioresistance. RUNX3 was downregulated and its promoter was hypermethylated in all radioresistant esophageal cancer cell lines examined. Stable transfection of esophageal cancer cells with RUNX3 slightly inhibited cell proliferation in vitro, enhanced the antiproliferative and apoptotic effects of TGF-b and increased radiosensitivity in conjunction with Bim induction. In contrast, transfection of RUNX3-expressing cells with a RUNX3 antisense construct or a Bim-specific small interfering RNA induced radioresistance. Treatment with 5-aza-2 0 -deoxycytidine restored RUNX3 expression, increased radiosensitivity and induced Bim in both control and radioresistant cells. These results suggest that RUNX3 silencing promotes radioresistance in esophageal cancers. Examination of RUNX3 expression in pretreatment specimens may predict radiosensitivity, and induction of RUNX3 expression may increase tumor radiosensitivity.

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Section: Discussionmentioning

confidence: 99%

Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis

et al. 2007

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“…Strikingly, the cDNA arrays showed that the disruption of Gli1 expression by small interfering RNA increased the expression of p21/CIP1 mRNA and protein. p21/CIP1 can induce G 1 arrest and block S-phase entry by inactivating CDKs (42) and the overexpression of p21/CIP1 effectively suppresses tumor growth (43). In addition, defects in p21/CIP1 increase susceptibility to chemically induced carcinoma formation (44).…”

Section: Discussionmentioning

confidence: 99%

p53-Independent Negative Regulation of p21/Cyclin-Dependent Kinase–Interacting Protein 1 by the Sonic Hedgehog-Glioma-Associated Oncogene 1 Pathway in Gastric Carcinoma Cells

et al. 2005

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The activation of Hedgehog (Hh) signaling has been implicated in the growth of various tumor types, including gastric carcinoma. However, the precise mechanisms of Hh activation and suppression of tumor growth by the blockade of Hh signaling in gastric carcinoma cells remain unknown. The aim of this study was to elucidate the mechanism of abnormal Hh signaling and the key molecules contributing to dysregulated growth of gastric carcinoma. The Sonic hedgehog (Shh) ligand and its receptor Patched were expressed in all five gastric carcinoma cell lines examined (MKN1, MKN7, MKN45, MKN74, and AGS cells). The blockade of Hh signaling with anti-Shh antibody inhibited the growth of all five gastric carcinoma cell lines. Shh was overexpressed (mean, 12.8-fold) in 8 of 14 (57.0%) cancerous tissue samples from patients with gastric carcinoma as compared with expression in the surrounding noncancerous tissues. The disruption of glioma-associated oncogene 1 (Gli1) by small interfering RNA induced an increase in p21/cyclin-dependent kinase-interacting protein 1 (CIP1), interfered with the G 1 -S transition, and suppressed cell proliferation. The stimulation or inhibition of Hh signaling did not affect p53 activity and the induction of p21/CIP1 expression and the G 1 arrest by inhibition of Hh signaling were not affected by the p53 status. These findings suggest that the overexpression of Shh contributes to constitutive Hh activation and that this signaling pathway negatively regulates p21/CIP1 through a Gli1-dependent and p53-independent mechanism in gastric carcinoma cells. (Cancer Res 2005; 65(23): 10822-9)

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“…However, since increased p53 expression is also observed following UV radiation treatment, additional studies will be necessary to clarify the relationship of PP5 and p53 in the response to UV radiation. Finally, recent studies indicate that the functional expression of the human p21 WAF1/Cip1 gene in rat glioma cells suppresses tumor growth in vivo (61), and the survival of patients with advanced gastric carcinoma correlates with the expression of p21 WAF1/Cip1 (59). When considered together with the data presented here, these studies indicate that inhibitors of PP5 gene expression, regardless of their mechanism of action, may be useful to elevate the level of p21 WAF1/Cip1 expression in cells harboring functional defects in p53, BRCA1, p73, and possibly other tumor suppressor protein-mediated pathways to restore G 1 checkpoint growth control.…”

Section: Discussionmentioning

confidence: 99%

Serine/Threonine Protein Phosphatase Type 5 Acts Upstream of p53 to Regulate the Induction of p21WAF1/Cip1 and Mediate Growth Arrest

Zuo¹,

Dean²,

Honkanen³

1998

Journal of Biological Chemistry

115

141

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Understanding how alterations in growth control pathways are translated into changes in the cell cycle regulatory machinery is a major challenge for understanding the development of human cancers. The ability of both tumor suppressor proteins, p53 and BRCA1, to induce the expression of p21 WAF1/Cip1 in combination with the inhibitory activity of p21 WAF1/Cip1 against cyclindependent kinases suggests that the regulation of p21 WAF1/Cip1 expression is an important aspect of mammalian cell cycle growth control. To elucidate the role of serine/threonine protein phosphatase type 5 (PP5) in processes regulating cell cycle progression, we developed antisense oligodeoxynucleotides targeted against PP5 (e.g. ISIS 15534) that specifically inhibit PP5 gene expression. Employing ISIS 15534, we demonstrate that the specific inhibition of PP5 gene expression has a marked antiproliferative effect on cells, characterized by induction of p21 WAF1/Cip1 and the subsequent arrest of cell growth. Investigations into the mechanisms leading to growth arrest reveal that, in the absence of PP5, the expression of p21 WAF1/Cip1 is induced in p53-competent A549 cells but not in p53 protein-deficient T-24 cells. Employing a stable cell line derived from p53-deficient human fibroblast that contains tetracycline-regulated transactivator and operator plasmids to control the expression of wild-type p53 (TR9-7 cells), we then show that the induction of p21 WAF1/Cip1 , which occurs in response to the inhibition of PP5 expression, requires the p53 protein. Additional studies indicate that PP5 acts upstream of p53, influencing both the phosphorylation state and the ability of p53 to bind DNA, without causing an increase in p53 gene transcription. Together these studies suggest that PP5 is a regulatory component of a signaling pathway that affords replicating cells G 1 checkpoint growth control and that it is the regulation of PP5 that, in turn, controls p53-mediated expression of p21 WAF1/Cip1 and growth arrest in this pathway. In addition, since the inhibition of PP5 gene expression has marked antiproliferative activity and the overexpression of p21 WAF1/Cip1 blocks the growth of tumor cells, these studies suggest that compounds that inhibit of PP5 gene expression may be useful in the treatment of human cancers.The reversible phosphorylation of serine and threonine residues on proteins is a mechanism utilized by eukaryotic cells to regulate the biological activity of many enzymes, and phosphorylation influences cellular events as diverse as metabolism, signal transduction, and cell cycle progression. Although the kinases involved in these processes are well recognized, the critical contribution of serine/threonine protein phosphatases (PPases) 1 has only been appreciated more recently (1, 2). Traditionally, mammalian PPases have been grouped into four subtypes (PP1, PP2A, PP2B, and PP2C) based on 1) their biochemical characteristics, 2) their sensitivities to specific inhibitors, and 3) a limited amount of substrate specificity that can be demonst...

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Functional Expression of Human p21WAF1/CIP1Gene in Rat Glioma Cells Suppresses Tumor Growthin Vivoand Induces Radiosensitivity

Cited by 41 publications

References 13 publications

Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis

Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis

p53-Independent Negative Regulation of p21/Cyclin-Dependent Kinase–Interacting Protein 1 by the Sonic Hedgehog-Glioma-Associated Oncogene 1 Pathway in Gastric Carcinoma Cells

Serine/Threonine Protein Phosphatase Type 5 Acts Upstream of p53 to Regulate the Induction of p21WAF1/Cip1 and Mediate Growth Arrest

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