P130 and its truncated form mediate p53-induced cell cycle arrest inRb−/− Saos2 cells

Gao, ChongFeng; Ren, Shuo; Wang, Jingfei; Zhang, Sheng-Liang; Jin, Feng; Nakajima, Takuma; Ikeda, Masa‐Aki; Tsuchida, Nobuo

doi:10.1038/sj.onc.1205933

Cited by 11 publications

(9 citation statements)

References 64 publications

(72 reference statements)

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“…Although the E2F-p130 complex is the most abundant in quiescent cells, the E2F-p107 and E2F-Rb complexes accumulate in G 1 cells but not in S, G 2 , or M phases (Moberg et al, 1996). Thus, p107, which is expressed by SaOS2 cells (Gao et al, 2002), may bypass the Rb defect in these cells and could explain the observed Zol effects.…”

Section: Zoledronic Acid Effects On Osteosarcoma Cell Lines 339mentioning

confidence: 98%

Zoledronic Acid Activates the DNA S-Phase Checkpoint and Induces Osteosarcoma Cell Death Characterized by Apoptosis-Inducing Factor and Endonuclease-G Translocation Independently of p53 and Retinoblastoma Status

Ory¹,

Blanchard²,

Battaglia³

et al. 2006

Mol Pharmacol

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The molecular mechanisms responsible for the cellular effects of the nitrogen-containing bisphosphonate zoledronic acid (Zol) were assessed on several osteosarcoma cell lines differing in their p53 and retinoblastoma (Rb) status. Zol inhibited cell proliferation and increased atypical apoptosis. The Zol effects on proliferation were due to cell cycle arrest in S and G 2 /M phases subsequent to the activation of the intra-S DNA damage checkpoint with an increase in P-ATR, P-chk1, Wee1, and P-cdc2 levels and a decrease in cdc25c, regardless of the p53 and Rb status. In addition, the atypic apoptosis induced by Zol was independent of caspase activation, and it was characterized by nuclear alterations, increased Bax expression, and reduced Bcl-2 level. Furthermore, mitochondrial permeability was up-regulated by Zol independently of p53 in association with the translocation of apoptosis-inducing factor (AIF) and endonuclease-G (EndoG). Zol also disturbed cytoskeletal organization and cell junctions and inhibited cell migration and phosphorylation of focal adhesion kinases. The main difficulty encountered in treating cancer relates to mutations in key genes such as p53, Rb, or proteins affecting caspase signaling carried by many tumor cells. We have demonstrated for the first time that zoledronic acid activated the DNA damage S-phase checkpoint and the mitochondrial pathway via AIF and EndoG translocation, and it inhibited cell proliferation and induced cell death, bypassing these potentials mutations. Therefore, zoledronic acid may be considered as an effective therapeutic agent in clinical trials of osteosarcoma in which mutation for p53 and Rb very often occur, and where current treatment with traditional chemotherapeutic agents is ineffective.Bisphosphonates (BPs) are stable synthetic analogs of the naturally occurring pyrophosphate (Heymann et al., 2004). Different side chains can be added to the central carbon atom, thus producing a range of BPs with varying clinical activity and potency . Therefore, BPs can be grouped into two classes of non-nitrogen-containing and nitrogen-containing BPs. The clinical use of bisphosphonates has increased dramatically during the past decade. The most common indicator for the use of these compounds is osteoporosis, but their use has rapidly emerged in osteolytic bone diseases characterized by enhanced bone resorption (e.g., Paget's disease and hypercalcemia of malignancy). Indeed, BPs are currently the most effective class of antiresorptive drugs available, and their first targets identified were osteoclasts. Due to the high tropism of BPs for hydroxyapatite in bone and the ability of osteoclasts to release bone-bound bisphosphonate, a direct effect on mature osteoclasts seems to be the most important mechanism of action. BPs can be grouped into two classes of non-nitrogen-containing and nitrogen-containing BPs. The BPs that lack a nitrogen atom and are most closely related to pyrophosphate (such as clodronate, etidronate, and tiludronate) are metabolized intracellular...

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Section: Zoledronic Acid Effects On Osteosarcoma Cell Lines 339mentioning

confidence: 98%

Zoledronic Acid Activates the DNA S-Phase Checkpoint and Induces Osteosarcoma Cell Death Characterized by Apoptosis-Inducing Factor and Endonuclease-G Translocation Independently of p53 and Retinoblastoma Status

Ory¹,

Blanchard²,

Battaglia³

et al. 2006

Mol Pharmacol

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“…p53 binds BAF53, and SWI/SNF activity is necessary for p53-mediated transcription activation and p53-mediated cell cycle control (Bochar et al, 2000;Wang et al, 2007). It has been reported that p53-mediated cell cycle arrest is dependent upon the RB family member p130 (Claudio et al, 2000;Gao et al, 2002;Kapic et al, 2006), which is known to bind BRG1 and BRM, and, by analogy with RB1, is likely to require SWI/SNF activity for function. Thus, the role of SWI/SNF in p53-mediated checkpoint control is likely to involve both p53 itself as well as downstream effectors of p53 signaling such as p130.…”

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confidence: 99%

The SWI/SNF complex and cancer

2009

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The mammalian SWI/SNF complexes mediate ATPdependent chromatin remodeling processes that are critical for differentiation and proliferation. Not surprisingly, loss of SWI/SNF function has been associated with malignant transformation, and a substantial body of evidence indicates that several components of the SWI/SNF complexes function as tumor suppressors. This review summarizes the evidence that underlies this conclusion, with particular emphasis upon the two catalytic subunits of the SWI/SNF complexes, BRM, the mammalian ortholog of SWI2/SNF2 in yeast and brahma in Drosophila, and Brahma-related gene-1 (BRG1).

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“…p53 growth inhibition depends on the function of the p130 tumor suppressor, which in turn requires the function of BRG1 and BRM. Hence, p130 binds and cooperates with these two SWI/SNF catalytic subunits in a fashion similar to Rb to mediate growth inhibition [66,67]. Therefore, p53-mediated growth inhibition is ultimately dependent on SWI/SNF functionality, and the loss of BRG1 and/or BRM would be expected to impair or block p53-mediated growth inhibition.…”

Section: Interactions and Functional Dependence Of Key Cellular Proteinsmentioning

confidence: 95%

Alteration to the SWI/SNF complex in human cancers

2010

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The SWI/SNF complex is a key catalyst for gene expression and regulates a variety of pathways, many of which have anticancer roles. Its central roles in cellular growth control, DNA repair, differentiation, cell adhesion and development are often targeted, and inactivated, during cancer development and progression. In this review, we will discuss what is known about how SWI/SNF is inactivated, and describe the potential impact of abrogating this complex. BRG1 and BRM are the catalytic subunits which are essential for SWI/SNF function, and thus, it is not surprising that they are lost in a variety of cancer types. As neither gene is mutated when lost, the mechanism of suppression, as well as the impact of potential gene activity restoration, are reviewed.

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P130 and its truncated form mediate p53-induced cell cycle arrest inRb−/− Saos2 cells

Cited by 11 publications

References 64 publications

Zoledronic Acid Activates the DNA S-Phase Checkpoint and Induces Osteosarcoma Cell Death Characterized by Apoptosis-Inducing Factor and Endonuclease-G Translocation Independently of p53 and Retinoblastoma Status

Zoledronic Acid Activates the DNA S-Phase Checkpoint and Induces Osteosarcoma Cell Death Characterized by Apoptosis-Inducing Factor and Endonuclease-G Translocation Independently of p53 and Retinoblastoma Status

The SWI/SNF complex and cancer

Alteration to the SWI/SNF complex in human cancers

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