Active Localization of the Retinoblastoma Protein in Chromatin and Its Response to S Phase DNA Damage

Avni, Dror; Yang, Hong; Martelli, Fabio; Hofmann, Francesco; ElShamy, Wael M.; Ganesan, Shridar; Scully, Ralph; Livingston, David M.

doi:10.1016/s1097-2765(03)00355-1

Cited by 107 publications

(114 citation statements)

References 49 publications

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“…It was speculated that, upon cell treatment with H 2 O 2 , Rb family members might bind in their dephosphorylated form directly to the DNA replication origins thereby inhibiting their firing (48). Indeed, upon DNA damage by ␥-irradiation, Rb binds to selected DNA replication origins, inhibiting DNA replication in S-phase (49). In this study we observed a decrease in the ratio of hyperphosphorylated Rb to hypophosphorylated Rb in the cells at the earliest time point (Fig.…”

Section: Cessation Of Dna Replication Is a Rapid Responsive Event In supporting

confidence: 51%

Loss of Proliferative Capacity and Induction of Senescence in Oxidatively Stressed Human Fibroblasts

Chen

Stoeber

Kingsbury

et al. 2004

Journal of Biological Chemistry

135

114

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Cellular senescence can result from short, dysfunctional telomeres, oxidative stress, or oncogene expression, and may contribute to aging. To investigate the role of cellular senescence in aging it is necessary to define the time-dependent molecular events by which it is characterized. Here we investigated changes in levels of key proteins involved in cell cycle regulation, DNA replication, and stress resistance in senescing human fibroblasts following oxidative stress. An immediate response in stressed cells was dephosphorylation of retinoblastoma (Rb) and cessation of DNA synthesis. This was followed by sequential induction of p53, p21, and p16. Increase in hypophosphorylated Rb and induction of p53 and p21 by a single stress treatment was transient, whereas sustained induction or dephosphorylation were achieved by a second stress. Down-regulation of the critical DNA replication initiation factor Cdc6 occurred early after stress concurring with p53 induction, and was followed by a decrease in Mcm2 levels. A late event in the stress-induced molecular sequence was the induction of SOD1, catalase, and HSP27 coinciding with development of the fully senescent phenotype. Our data suggest that loss of proliferative capacity in oxidatively stressed cells is a multistep process regulated by time-dependent molecular events that may play differential roles in induction and maintenance of cellular senescence.

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Section: Cessation Of Dna Replication Is a Rapid Responsive Event In supporting

confidence: 51%

Loss of Proliferative Capacity and Induction of Senescence in Oxidatively Stressed Human Fibroblasts

Chen

Stoeber

Kingsbury

et al. 2004

Journal of Biological Chemistry

135

114

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“…Since ectopic SET expression antagonised the effects of exogenous PP2A, it is possible that, in CML-BC progenitors, SET-dependent suppression of PP2A activity represents one of the main mechanisms used by BCR/ABL to prevent inactivation of mitogenic and survival signals required for its leukaemogenic activity. The importance of loss of PP2A activity for CML disease progression is also supported by the ability of PP2A to induce Rb dephosphorylation (Avni et al, 2003) and suppress Jak2 kinase, which was found activated in CML-BC (Xie et al, 2002).…”

Section: Adverse Molecular Effects Of Bcr/abl and Pp2amentioning

confidence: 91%

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL þ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

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“…Rb family and DNA damage response: how cell cycle regulation helps DNA repair Rb is recruited to certain replication initiation sites after DNA damage, presumably to suppress abnormal replication activity (Avni et al, 2003). It is uncertain whether E2F and Rb directly regulate DNA replication during the normal cell cycle progression or whether their functions are restricted only to certain situations, such as in response to DNA damage.…”

Section: Cell Cycle Checkpointsmentioning

confidence: 99%

Cell cycle control and beyond: emerging roles for the retinoblastoma gene family

et al. 2006

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Rb family proteins (pRb/p105, Rb2/p130 and p107) play a key role in cell cycle control and are worthily involved in transcription repression and tumor suppression. The mechanisms of transcriptional activation and repression by the Rb gene family has been extensively investigated: pRb, pRb2/p130 and p107 interact with different E2F family factors and can inhibit E2F responsive promoters, interfering with progression of cell cycle, gene transcription, initiation of apoptotic process and cell differentiation. Recent studies have indicated that Rb and Rb2/p130 may be involved in cellular response to DNA damage events, by influencing the transcription of factors involved in DNA repair pathways. In particular, evidences suggest that Rb loss and target gene deregulation impacts on the repair of UV-induced pyrimidine pyrimidone photoproducts (6-4 PP) by regulating the expression of several DNA damage factors involved in UV DNA damage repair processes, including proliferating cell nuclear antigen. Ongoing studies are focused on the mechanisms by which Rb family genes drive cell cycle exit following DNA damage induction, and how Rb gene family's interaction with chromatin remodeling factors can influence DNA repair dynamics.

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Active Localization of the Retinoblastoma Protein in Chromatin and Its Response to S Phase DNA Damage

Cited by 107 publications

References 49 publications

Loss of Proliferative Capacity and Induction of Senescence in Oxidatively Stressed Human Fibroblasts

Loss of Proliferative Capacity and Induction of Senescence in Oxidatively Stressed Human Fibroblasts

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Cell cycle control and beyond: emerging roles for the retinoblastoma gene family

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