Inactivation of p53 in a Human Ovarian Cancer Cell Line Increases the Sensitivity to Paclitaxel by Inducing G2/M Arrest and Apoptosis

Vikhanskaya, Faina; Vignati, Sara; Beccaglia, Patrizia; Ottoboni, Cristina; Russo, Patrizia; D’Incalci, Maurizio; Broggini, Massimo

doi:10.1006/excr.1998.4018

Cited by 79 publications

(50 citation statements)

References 20 publications

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“…80 -85 Interestingly, of the three astrocytoma cell lines examined in this study, U87 and U343 express wild-type p53 whereas U373 is mutant for p53. 26,27,80 -86 As there have been several cancer cell systems in which apoptosis has been demonstrated in p53-inactivated cells, [87][88][89][90][91][92][93][94][95][96] it is conceivable that the apoptosis observed in U373 C3 cells after p57 induction occurs in a p53-independent manner. We showed that Bax levels were unchanged but PARP levels were decreased without cleavage formation after p57 induction in all cell clones.…”

Section: Discussionmentioning

confidence: 99%

Expression of p57KIP2 Potently Blocks the Growth of Human Astrocytomas and Induces Cell Senescence

Tsugu

Sakai

Dirks

et al. 2000

The American Journal of Pathology

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Astrocytic tumors frequently exhibit defects in the expression or activity of proteins that control cellcycle progression. Inhibition of kinase activity associated with cyclin/cyclin-dependent kinase co-complexes by cyclin-dependent kinase inhibitors is an important mechanism by which the effects of growth signals are down-regulated. We undertook the present study to determine the role of p57 KIP2 (p57) in human astrocytomas. We demonstrate here that whereas p57 is expressed in fetal brain tissue, specimens of astrocytomas of varying grade and permanent astrocytoma cell lines do not express p57, and do not contain mutations of the p57 gene by multiplex-heteroduplex analysis. However, the inducible expression of p57 in three well-characterized human astrocytoma cell lines (U343 MG-A, U87 MG, and U373 MG) using the tetracycline repressor system leads to a potent proliferative block in G 1 as determined by growth curve and flow cytometric analyses. After the induction of p57, retinoblastoma protein, p107, and E2F-1 levels diminish, and retinoblastoma protein is shifted to a hypophosphorylated form. Morphologically, p57-induced astrocytoma cells became large and flat with an expanded cytoplasm. The inducible expression of p57 leads to the accumulation of senescence-associated ␤-galactosidase marker within all astrocytoma cell lines such that ϳ75% of cells were positive at 1 week after induction. Induction of p57 in U373 astrocytoma cells generated a small population of cells (ϳ15%) that were nonviable, contained discrete nuclear fragments on The most common brain tumor is the astrocytoma accounting for ϳ65% of all primary brain tumors. The malignant astrocytoma has a very poor prognosis primarily because of its highly proliferative and invasive nature. As with other neoplasms with increased proliferative potential, malignant astrocytomas demonstrate dysregulation of various components of the cell cycle machinery. Altered expression of positive growth regulators such as growth factors, cyclins, and cyclin-dependent kinases (CDKs), or the loss of negative regulators, including cyclin-dependent kinase inhibitors (CKIs) and the retinoblastoma protein (pRB) have all been demonstrated in malignant astrocytomas. 1,2 The CDKs phosphorylate pRB to release cells from cell-cycle arrest. In contrast with CDKs, the CKIs inhibit cyclin-CDK complexes and transduce internal or external growth suppressive signals. Accordingly, all CKIs may be construed as candidate tumor suppressor genes.The CKIs are divided into two families, the INK4 and the CIP/KIP, which are defined on the basis of their structural homology and mechanism of action. The CIP/KIP family includes three structurally related members, p21 CIP1/WAF1 , 3,4 p27 KIP1 , 5,6 and a recently isolated and cloned third member, p57 KIP2 (p57). 7-10 These three CKIs share a common N-terminal domain for binding to and inhibiting the kinase activity of CDK-cyclin complexes. Mouse p57 consists of four structurally distinct domains, a CDK inhibitory domain, a proline-rich domain, an a...

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Section: Discussionmentioning

confidence: 99%

Expression of p57KIP2 Potently Blocks the Growth of Human Astrocytomas and Induces Cell Senescence

Tsugu

Sakai

Dirks

et al. 2000

The American Journal of Pathology

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“…21 More importantly, loss of normal p53 function has been demonstrated to sensitize patients to paclitaxel. 19,[22][23][24] Because mutations of p53 are present in more than 60% of human cancers, 16 these data highlight a unique advantage of paclitaxel in cancer therapy.…”

Section: Paclitaxel-induced Apoptosis and P53 Statusmentioning

confidence: 99%

Paclitaxel-induced cell death

Wang

Soong

2000

Cancer

562

185

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“…Several reports have supported this paradigm (Janicke et al, 2008;Gudkov and Komarova, 2010). For example, absence of p53 has been shown to promote taxol-mediated death owing to failure of cell arrest in the G 1 phase of the cell cycle, and hence, allowing cells to accumulate in the G 2 /M phase where they undergo mitotic cell death (Vikhanskaya et al, 1998). In addition, cells with wild-type p53 have been shown to be more resistant to cytotoxic drug treatment in some cases (Hermisson et al, 2006;Batista et al, 2007;Roos et al, 2007).…”

Section: Introductionmentioning

confidence: 96%

p53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1

Nam

Sabapathy

2011

Oncogene

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Inactivation of p53 in a Human Ovarian Cancer Cell Line Increases the Sensitivity to Paclitaxel by Inducing G2/M Arrest and Apoptosis

Cited by 79 publications

References 20 publications

Expression of p57KIP2 Potently Blocks the Growth of Human Astrocytomas and Induces Cell Senescence

Expression of p57KIP2 Potently Blocks the Growth of Human Astrocytomas and Induces Cell Senescence

Paclitaxel-induced cell death

p53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1

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