Cytoplasmic translocation of the retinoblastoma protein disrupts sarcomeric organization

Araki, Keigo; Kawauchi, Keiko; Harai, Hiroaki; Yamamoto, Mie

doi:10.7554/elife.01228

Cited by 14 publications

(14 citation statements)

References 45 publications

(62 reference statements)

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“…Importantly, inhibition of autophagy rescues this phenotype even in the absence of pRB function (51). Intriguingly, Araki et al have recently demonstrated that loss of nuclear localization by pRB interferes with sarcomere structure in skeletal muscle, leading to a nonapoptotic cell death (52). This may offer a nontranscriptional explanation of our phenotype, as loss of E2F binding likely reduces pRB anchorage in the nucleus.…”

Section: Discussionmentioning

confidence: 79%

A Retinoblastoma Allele That Is Mutated at Its Common E2F Interaction Site Inhibits Cell Proliferation in Gene-Targeted Mice

Cecchini

Thwaites

Talluri

et al. 2014

Molecular and Cellular Biology

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fThe retinoblastoma protein (pRB) is best known for regulating cell proliferation through E2F transcription factors. In this report, we investigate the properties of a targeted mutation that disrupts pRB interactions with the transactivation domain of E2Fs. Mice that carry this mutation endogenously (Rb1 ⌬G ) are defective for pRB-dependent repression of E2F target genes. Except for an accelerated entry into S phase in response to serum stimulation, cell cycle regulation in Rb1 ⌬G/⌬G mouse embryonic fibroblasts (MEFs) strongly resembles that of the wild type. In a serum deprivation-induced cell cycle exit, Rb1⌬G/⌬G MEFs display a magnitude of E2F target gene derepression similar to that of Rb1 ؊/؊ cells, even though Rb1 ⌬G/⌬G cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1 ⌬G/⌬G MEFs is responsive to p16 expression and gamma irradiation, indicating that alternate mechanisms can be activated in G 1 to arrest proliferation. Some Rb1 ⌬G/⌬G mice die neonatally with a muscle degeneration phenotype, while the others live a normal life span with no evidence of spontaneous tumor formation. Most tissues appear histologically normal while being accompanied by derepression of pRB-regulated E2F targets. This suggests that non-E2F-, pRB-dependent pathways may have a more relevant role in proliferative control than previously identified.T he retinoblastoma tumor suppressor protein (pRB) has a central role in the regulation of the G 1 -to-S-phase transition. Inactivation of its control over cell cycle progression is one of the most common events in cancer (1). The RB protein is thought to regulate entry into S phase through its ability to repress E2F-dependent transcription (2). In the G 1 phase of the cell cycle, a direct interaction between the large pocket domain of pRB (RBLP) and the transactivation domain of E2Fs blocks transcription and recruits chromatin regulators that maintain the cell in G 1 (3). Activation of cyclin-dependent kinases (CDKs) results in the phosphorylation of pRB and the release of E2F transcription factors (4). Free E2Fs then activate a transcriptional program that drives the cell into S phase (3). This model of pRB regulation of E2F dominates our understanding of G 1 -to-S-phase control. Much of our knowledge of this model was derived from studies using viral oncoproteins encoded by small DNA tumor viruses (5, 6). Of particular note, the human papillomavirus E7 protein has been shown to compete for pRB-E2F interactions to deregulate proliferation (7, 8). However, E7 must also target pRB for degradation in order to induce proliferation (8). Thus, the experimental system that gave rise to the pRB-E2F regulatory axis in cell cycle control also suggests that pRB may engage other growth-suppressing activities beyond E2F regulation. By comparison with the pRB-E2F pathway, we know very little about pRB's non-E2F-dependent growth control mechanisms and their relative contribution to cell cycle regulation and tumor suppressor activities.The minimal growth-suppressive region of pRB...

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Section: Discussionmentioning

confidence: 79%

A Retinoblastoma Allele That Is Mutated at Its Common E2F Interaction Site Inhibits Cell Proliferation in Gene-Targeted Mice

Cecchini

Thwaites

Talluri

et al. 2014

Molecular and Cellular Biology

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“…Thus, the physiological function of Rb consists of two independent circuits (Figure S6D): hypo-phosphorylated Rb mainly binds and suppresses E2F1 to arrest cell cycle at G1 phase, while the hyper-phosphorylated species of Rb become loosely interacted with chromatin and partly translocates into the cytoplasm to bind and inhibit mTORC2 towards activating the Akt oncogenic signaling pathways. However, as Rb can impact mitochondrial biogenesis and function in cytoplasm (Araki et al, 2013; Attardi and Sage, 2013; Hilgendorf et al, 2013; Nicolay et al, 2015), future study is warranted to explore whether hyper-phosphorylated Rb also can indirectly affect mTORC2 through regulating mitochondrial functions.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the canonical function of Rb in regulating cell cycle progression in the nucleus, recent studies have also started to reveal a possible physiological role of Rb in the cytoplasm, such as regulating mitochondrial functions and disrupting sarcomeric organization (Araki et al, 2013; Hilgendorf et al, 2013; Nicolay et al, 2015). In support of these findings, the hyper-phosphorylated form of Rb has been observed in the cytoplasm of human cancers (Jiao et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt

Zhang

Liu

et al. 2016

Molecular Cell

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SUMMARY The retinoblastoma (Rb) protein exerts its tumor suppressor function primarily by inhibiting the E2F family of transcription factors that govern cell cycle progression. However, it remains largely elusive whether hyper-phosphorylated, non-E2F1-interacting form, of Rb has any physiological role. Here, we report that hyper-phosphorylated Rb directly binds to, and suppresses the function of mTORC2, but not mTORC1. Mechanistically, Rb, but not p107 nor p130, interacts with Sin1 and blocks the access of Akt to mTORC2, leading to attenuated Akt activation and increased sensitivity to chemotherapeutic drugs. As such, inhibition of Rb phosphorylation by depleting cyclin D, or using CDK4/6 inhibitors, releases Rb-mediated mTORC2 suppression. This, in turn, leads to elevated Akt activation to confer resistance to chemotherapeutic drugs in Rb-proficient cells, which can be attenuated with Akt inhibitors. Therefore, our work provides a molecular basis for the synergistic usage of CDK4/6 and Akt inhibitors in treating Rb-proficient cancer. Zhang et al report that hyper-phosphorylated Rb also plays a tumor suppressive role partly through binding Sin1 to inhibit mTORC2-mediated activation of Akt. Thus, inhibiting Rb phosphorylation by depletion of cyclin D or CDK4/6 inhibitor leads to elevated Akt-pS473 to confer drug resistance, which can be attenuated by Akt inhibitors.

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“…We reported recently that Rb causes disruption of the sarcomeric structure of skeletal muscle myotubes via its interaction with the formin protein mDia1 [113], an effector of RhoA [114]. This pathway is stimulated by the inflammatory cytokine TNF α .…”

Section: Rb Regulates Cell Adhesion Molecules and Downstream Pathwaysmentioning

confidence: 99%

“…Cytoplasmic Rb might contribute to cancer progression by promoting muscle atrophy. Indeed, cytoplasmic Rb was detected in atrophied tibialis anterior muscles, but not the normal muscles, of cancer patients [113]. …”

Section: Rb Regulates Cell Adhesion Molecules and Downstream Pathwaysmentioning

confidence: 99%

Functions of the Tumor Suppressors p53 and Rb in Actin Cytoskeleton Remodeling

Ebata

Harai

Kawauchi

2016

BioMed Research International

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Mechanical microenvironments, such as extracellular matrix stiffness and strain, have crucial roles in cancer progression. Cells sense their microenvironments with mechanosensing biomolecules, which is accompanied by the modulation of actin cytoskeleton structures, and the signals are subsequently transduced downstream as biochemical signals. The tumor suppressors p53 and retinoblastoma protein (Rb) are known to prevent cancer progression. The p53 and Rb signaling pathways are disrupted in many types of cancers. Here, we review recent findings about the roles of these tumor suppressors in the regulation of mechanosensing biomolecules and the actin cytoskeleton. We further discuss how dysfunction in the p53- and/or Rb-mediated mechanosignaling pathways is potentially involved in cancer progression. These pathways might provide good targets for developing anticancer therapies.

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Cytoplasmic translocation of the retinoblastoma protein disrupts sarcomeric organization

Cited by 14 publications

References 45 publications

A Retinoblastoma Allele That Is Mutated at Its Common E2F Interaction Site Inhibits Cell Proliferation in Gene-Targeted Mice

A Retinoblastoma Allele That Is Mutated at Its Common E2F Interaction Site Inhibits Cell Proliferation in Gene-Targeted Mice

Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt

Functions of the Tumor Suppressors p53 and Rb in Actin Cytoskeleton Remodeling

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