Dephosphorylation of threonine-821 of the retinoblastoma tumor suppressor protein (Rb) is required for apoptosis induced by UV and Cdk inhibition

Lentine, Brandon; Antonucci, Lisa; Hunce, Ray; Edwards, Justina; Marallano, Valerie; Krucher, Nancy A.

doi:10.4161/cc.21693

Cited by 27 publications

(17 citation statements)

References 46 publications

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“…RB is a key regulator of multiple cellular functions including cell proliferation, apoptosis, differentiation, genome integrity, quiescence, senescence and DNA repair (3-6). RB function is altered in several tumor types through distinct mechanisms, which are often tissue specific.…”

Section: Introductionmentioning

confidence: 99%

The Retinoblastoma Tumor Suppressor Modulates DNA Repair and Radioresponsiveness

Thangavel

Boopathi

Ciment

et al. 2014

Clinical Cancer Research

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Purpose Perturbations in the RB pathway are overrepresented in advanced prostate cancer; RB loss promotes bypass of first line hormone therapy. Conversely, preliminary studies suggested that RB-deficient tumors may become sensitized to a subset of DNA damaging agents. Here, the molecular and in vivo consequence of RB status was analyzed in models of clinical relevance. Experimental Design Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAPC4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of RB using shRNA). Multiple mechanisms were interrogated including cell cycle, apoptosis, and DNA damage repair. Transcriptome analysis was performed, validated, and mechanisms discerned. Cell survival was measured using clonogenic cell survival assay and in vivo analysis was performed in nude mice with human derived tumor xenografts. Results Loss of RB enhanced the radioresponsiveness of both hormone sensitive and castrate resistant prostate cancer. Hypersensitivity to ionizing radiation was not mediated by cell cycle or p53. RB loss led to alteration in DNA damage repair and activation of the NFκB pathway and subsequent cellular apoptosis through PLK3. In vivo xenografts of RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with ionizing radiation (p<0.05). Conclusions Loss of RB confers increased radiosensitivity in prostate cancer. This hypersensitization was mediated by alterations in apoptotic signaling. Combined, these not only provide insight into the molecular consequence of RB loss, but also credential RB status as a putative biomarker for predicting response to radiation therapy.

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Section: Introductionmentioning

confidence: 99%

The Retinoblastoma Tumor Suppressor Modulates DNA Repair and Radioresponsiveness

Thangavel

Boopathi

Ciment

et al. 2014

Clinical Cancer Research

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“…PP1 and PP2A also dephosphorylate Rb in response to different cellular stresses [53]. Although this dephosphorylation is usually global, in one case, hypoxia and DNA damage were observed to result specifically in T821 dephosphorylation [55]. T821 is not efficiently dephosphorylated at mitotic exit, indicating that it plays a role in Rb-mediated stress response, rather than normal cell cycle regulation [54, 55].…”

Section: Code Writing: Mechanisms For Controlling Rb Phosphorylationmentioning

confidence: 99%

Deciphering the retinoblastoma protein phosphorylation code

Rubin

2013

Trends in Biochemical Sciences

225

199

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Multisite phosphorylation modulates the function of regulatory proteins with complex signaling properties and outputs. The retinoblastoma tumor suppressor protein (Rb) is inactivated by Cyclin-dependent kinase (Cdk) phosphorylation in normal and cancer cell cycles, so understanding the molecular mechanisms and effects of Rb phosphorylation is imperative. Rb functions in diverse processes regulating proliferation, and it has been speculated that multisite phosphorylation might act as a code in which discrete phosphorylations control specific activities. The idea of an Rb phosphorylation code is evaluated here in light of recent studies of Rb structure and function. Rb inactivation is discussed with an emphasis on how multisite phosphorylation changes Rb structure and associations with protein partners.

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“…Drug treatment affects the cell cycle and cell proliferation at the late cellular response Figure S4F). This downregulation induces binding of RB1 to E2F1 thereby inhibiting E2F1 activity (Lentine et al, 2012), and promoting cell cycle arrest (Henley & Dick, 2012) under BRAFi conditions at the late timepoints. Further enrichment analysis of the MSigDB hallmarks gene-sets revealed enrichment for proliferation-related gene sets including E2F targets, genes involed in the G2M checkpoint, and mitotic spindle genes (Table S2).…”

Section: System-wide Propagation Of Drug Perturbationmentioning

confidence: 99%

A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells

Ressa

Bosdriesz²,

Ligt

et al. 2017

Preprint

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Intrinsic and/or acquired resistance represents one of the great challenges in targeted cancer therapy. A deeper understanding of the molecular biology of cancer has resulted in more 16 efficient strategies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has also been observed in colorectal cancer patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block intrinsic resistance to BRAF inhibitors. Here, we investigate molecular responses upon single and multitarget treatments, over time, using BRAF(V600E) mutant colorectal cancer cells as a model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both known and novel responses. We primarily observe widespread upregulation of receptors tyrosine kinases and metabolic pathways upon BRAF inhibition. These findings point to mechanisms by which the drug-treated cells switch energy sources and enter a quiescent-like state as a defensive response, while additionally reactivating the MAPK pathway.

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Dephosphorylation of threonine-821 of the retinoblastoma tumor suppressor protein (Rb) is required for apoptosis induced by UV and Cdk inhibition

Cited by 27 publications

References 46 publications

The Retinoblastoma Tumor Suppressor Modulates DNA Repair and Radioresponsiveness

The Retinoblastoma Tumor Suppressor Modulates DNA Repair and Radioresponsiveness

Deciphering the retinoblastoma protein phosphorylation code

A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells

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