Discrete signaling pathways participate in RB-dependent responses to chemotherapeutic agents

Mayhew, Christopher N.; Perkin, Lisa M; Zhang, Xiaoping; Sage, Julien; Jacks, Tyler; Knudsen, Erik S.

doi:10.1038/sj.onc.1207503

Cited by 43 publications

(54 citation statements)

References 74 publications

(92 reference statements)

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“…A Masselli and JYJ Wang consistent with previous observations that RB promotes cell cycle arrest and inhibits apoptosis in response to DNA damage (Knudsen et al, 2000;Bosco et al, 2004;Mayhew et al, 2004). It is well established that dephosphorylated RB (such as PSM-RB) represses E2F-regulated promoters, including those of proapoptotic genes such as caspase-3 and Apaf-1 (Muller et al, 2001).…”

Section: Negative and Positive Effects Of Pms-rb On Apoptosissupporting

confidence: 83%

Phosphorylation site mutated RB exerts contrasting effects on apoptotic response to different stimuli

Masselli

Wang

2005

Oncogene

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The retinoblastoma tumor-suppressor protein (RB) is an important regulator of cell cycle and apoptosis. RB is phosphorylated by cyclin-dependent protein kinase during cell cycle progression. A phosphorylation site mutated (PSM)-RB has previously been shown to cause G1 arrest and to interfere with S phase progression. In this study, we examined the effect of inducible PSM-RB expression on the apoptotic response to three different death stimuli: doxorubicin (DOXO), staurosporine (STS) and tumor necrosis factor (TNF) in Rat-16 cells. Induced expression of PSM-RB attenuated caspase activation by DOXO as a result of cell cycle arrest. STS has been shown to cause RB-dependent G1 arrest or apoptosis; however, expression of PSM-RB did not prevent caspase activation by STS. Surprisingly, induced expression of PSM-RB stimulated the apoptotic response to TNF in Rat-16 cells, which mostly undergo necrosis in the absence of PSM-RB. These results show that PSM-RB exerts disparate effects on apoptotic response to different stimuli, and that cell cycle arrest does not always associate with resistance to apoptosis.

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Section: Negative and Positive Effects Of Pms-rb On Apoptosissupporting

confidence: 83%

Phosphorylation site mutated RB exerts contrasting effects on apoptotic response to different stimuli

Masselli

Wang

2005

Oncogene

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“…However, many ER-positive patients develop resistance to antiestrogen therapy, and an alternative line of therapy such as either radiation or chemotherapy is required. It has been found in primary cells that the RB/E2F pathway plays an important role in mediating cell-cycle inhibition following exposure to such agents (29,30). In several breast cancer cell lines, we…”

Section: Discussionmentioning

confidence: 91%

The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer

et al. 2007

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The retinoblastoma tumor suppressor (RB) protein is functionally inactivated in the majority of human cancers and is aberrant in one-third of all breast cancers. RB regulates G 1 /S-phase cell-cycle progression and is a critical mediator of antiproliferative signaling. Here the specific impact of RB deficiency on E2F-regulated gene expression, tumorigenic proliferation, and the response to 2 distinct lines of therapy was investigated in breast cancer cells. RB knockdown resulted in RB/E2F target gene deregulation and accelerated tumorigenic proliferation, thereby demonstrating that even in the context of a complex tumor cell genome, RB status exerts significant control over proliferation. Furthermore, the RB deficiency compromised the short-term cell-cycle inhibition following cisplatin, ionizing radiation, and antiestrogen therapy. In the context of DNA-damaging agents, this bypass resulted in increased sensitivity to these agents in cell culture and xenograft models. In contrast, the bypass of antiestrogen signaling resulted in continued proliferation and xenograft tumor growth in the presence of tamoxifen. These effects of aberrations in RB function were recapitulated by ectopic E2F expression, indicating that control of downstream target genes was an important determinant of the observed responses. Specific analyses of an RB gene expression signature in 60 human patients indicated that deregulation of this pathway was associated with early recurrence following tamoxifen monotherapy. Thus, because the RB pathway is a critical determinant of tumorigenic proliferation and differential therapeutic response, it may represent a critical basis for directing therapy in the treatment of breast cancer.

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“…Therefore, we utilized a cell culture system wherein RB can be inactivated acutely. In this system, adult fibroblasts of Rb loxP/loxP mice are isolated and cultured (Mayhew et al, 2004). Infection of these cells with adenoviruses encoding Cre recombinase led to a rapid and efficient recombination of the Rb gene ( Figure 4a).…”

Section: Acute Rb Loss Deregulates Gene Expressionmentioning

confidence: 99%

“…The Rb N750F/N750F mice were generated using standard gene targeting approaches and expression of the allele confirmed (Bergseid and Wang, in preparation). Adult fibroblasts from Rb exon 3 loxP/loxP mice were cultured as previously described (Mayhew et al, 2004). MAFs were grown to passage three, infected with adenovirus encoding either GFP or GFP-Cre and cultured for 72 or 144 h postinfection.…”

Section: Cell Culturementioning

confidence: 99%

Loss of the retinoblastoma tumor suppressor: differential action on transcriptional programs related to cell cycle control and immune function

et al. 2007

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Functional inactivation of the retinoblastoma tumor suppressor gene product (RB) is a common event in human cancers. Classically, RB functions to constrain cellular proliferation, and loss of RB is proposed to facilitate the hyperplastic proliferation associated with tumorigenesis. To understand the repertoire of regulatory processes governed by RB, two models of RB loss were utilized to perform microarray analysis. In murine embryonic fibroblasts harboring germline loss of RB, there was a striking deregulation of gene expression, wherein distinct biological pathways were altered. Specifically, genes involved in cell cycle control and classically associated with E2F-dependent gene regulation were upregulated via RB loss. In contrast, a program of gene expression associated with immune function and response to pathogens was significantly downregulated with the loss of RB. To determine the specific influence of RB loss during a defined period and without the possibility of developmental compensation as occurs in embryonic fibroblasts, a second system was employed wherein Rb was acutely knocked out in adult fibroblasts. This model confirmed the distinct regulation of cell cycle and immune modulatory genes through RB loss. Analyses of ciselements supported the hypothesis that the majority of those genes upregulated with RB loss are regulated via the E2F family of transcription factors. In contrast, those genes whose expression was reduced with the loss of RB harbored different promoter elements. Consistent with these analyses, we found that disruption of E2F-binding function of RB was associated with the upregulation of gene expression. In contrast, cells harboring an RB mutant protein (RB-750F) that retains E2F-binding activity, but is specifically deficient in the association with LXCXE-containing proteins, failed to upregulate these same target genes. However, downregulation of genes involved in immune function was readily observed with disruption of the LXCXE-binding function of RB.Thus, these studies demonstrate that RB plays a significant role in both the positive and negative regulations of transcriptional programs and indicate that loss of RB has distinct biological effects related to both cell cycle control and immune function.

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Discrete signaling pathways participate in RB-dependent responses to chemotherapeutic agents

Cited by 43 publications

References 74 publications

Phosphorylation site mutated RB exerts contrasting effects on apoptotic response to different stimuli

Phosphorylation site mutated RB exerts contrasting effects on apoptotic response to different stimuli

The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer

Loss of the retinoblastoma tumor suppressor: differential action on transcriptional programs related to cell cycle control and immune function

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