Disrupting the DREAM transcriptional repressor complex induces apolipoprotein overexpression and systemic amyloidosis in mice

Perampalam, Pirunthan; Hassan, Haider M.; Lilly, Grace E.; Passos, Daniel Thompsen; Torchia, Joseph; Kiser, Patti; Božović, Andrea; Kulasingam, Vathany; Dick, Frederick A.

doi:10.1172/jci140903

Cited by 8 publications

(8 citation statements)

References 63 publications

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“…The three members of the RB family, RB1, RBL1/p107 and RBL2/p130, are key regulators of the cell cycle [ 47 ] and their dysregulation is strongly associated with tumor initiation and progression [ 1 , 48 ]. RB proteins restrain the cell cycle and inhibit the G1/S phase transition by interacting with the E2F transcription factors or forming the DREAM complex [ 2 , 17 ]. RB1/p105 binds and inhibits the transcriptional activators E2F1, E2F2 and E2F3, whereas RBL1/p107 and RBL2/p130 recruit the transcriptional repressors E2F4 and E2F5 to the nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…The nuclear function of RBL1/p107 is not fully elucidated. However, it has been suggested that RBL1/p107 can bind to the repressor E2F4, forming DREAM-like complexes [ 2 ] and might contribute to the repression of both G1/S and G2/M genes [ 16 ]. An increase in nuclear and hypophosphorylated RBL1/p107 might contribute to enhance RBL1/p107 binding to transcriptional repressors and their localization at promoters of G1/S genes or G2/M genes ( Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

“…RB proteins are key components of the cell cycle machinery and play a central role in regulating cell proliferation [ 1 ]. RB proteins restrain the cell cycle and act as tumor suppressors by interacting with the E2F transcription factors and, in the case of RBL2/p130 and RBL1/p107, by binding to the Multivulva class B (MuVB) core to form the transcriptional repressor DREAM (DP, Rb-like, E2F and MuvB) complex [ 2 , 3 ]. In addition, RB proteins antagonize the function of cycling-dependent kinases (CDK)s and regulate chromatin organization by interacting with histone-modifying enzymes and chromatin-regulating proteins [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, it has been recently reported that variants mapping to RBL1 correlated with tumor T cell subset abundance [ 14 ]. Similarly to RBL2/p130, RBL1/p107 binds to the repressors E2F4 and E2F5 [ 15 ] and, in the absence of RBL2/p130, it is able to assemble into DREAM-like complexes but it is not clearly defined whether these repressor complexes are functional [ 2 , 16 , 17 ]. In addition, it has been demonstrated that upon DNA damage and p53 activation, RB1/p105 and RBL2/p130 repress the expression of G1/S genes whereas RBL2/p130 and RBL1/p107 repress G2/M genes [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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RBL1/p107 Expression Levels Are Modulated by Multiple Signaling Pathways

Ventura

Iannuzzi

Pentimalli

et al. 2021

Cancers

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The members of the retinoblastoma (RB) protein family, RB1/p105, retinoblastoma-like (RBL)1/p107 and RBL2/p130 are critical modulators of the cell cycle and their dysregulation has been associated with tumor initiation and progression. The activity of RB proteins is regulated by numerous pathways including oncogenic signaling, but the molecular mechanisms of these functional interactions are not fully defined. We previously demonstrated that RBL2/p130 is a direct target of AKT and it is a key mediator of the apoptotic process induced by AKT inhibition. Here we demonstrated that RBL1/p107 levels are only minorly modulated by the AKT signaling pathway. In contrast, we discovered that RBL1/p107 levels are regulated by multiple pathways linked directly or indirectly to Ca2+-dependent signaling. Inhibition of the multifunctional calcium/calmodulin-dependent kinases (CaMKs) significantly reduced RBL1/p107 expression levels and phosphorylation, increased RBL1/p107 nuclear localization and led to cell cycle arrest in G0/G1. Targeting the Ca2+-dependent endopeptidase calpain stabilized RBL1/p107 levels and counteracted the reduction of RBL1/p107 levels associated with CaMKs inhibition. Thus, these novel observations suggest a complex regulation of RBL1/p107 expression involving different components of signaling pathways controlled by Ca2+ levels, including CaMKs and calpain, pointing out a significant difference with the mechanisms modulating the close family member RBL2/p130.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

RBL1/p107 Expression Levels Are Modulated by Multiple Signaling Pathways

Ventura

Iannuzzi

Pentimalli

et al. 2021

Cancers

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“…ApoA-IV is an early marker of renal impairment [ 108 ]. Recently, Perampalam et al reported that the downregulation of Dp, Rb-like, E2F and MuvB (DREAM), a transcriptional repressor, enhances ApoA4 protein levels and causes systemic amyloidosis in the heart, spleen, liver and kidneys [ 118 ]. ApoA-IV is also associated with changes in insulin resistance [ 119 ], which in turn are associated with CKD.…”

Section: Roles and Biological And Pathological Functions Of Apolipopr...mentioning

confidence: 99%

The Roles of Fatty Acids and Apolipoproteins in the Kidneys

Pan

2022

Metabolites

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The kidneys are organs that require energy from the metabolism of fatty acids and glucose; several studies have shown that the kidneys are metabolically active tissues with an estimated energy requirement similar to that of the heart. The kidneys may regulate the normal and pathological function of circulating lipids in the body, and their glomerular filtration barrier prevents large molecules or large lipoprotein particles from being filtered into pre-urine. Given the permeable nature of the kidneys, renal lipid metabolism plays an important role in affecting the rest of the body and the kidneys. Lipid metabolism in the kidneys is important because of the exchange of free fatty acids and apolipoproteins from the peripheral circulation. Apolipoproteins have important roles in the transport and metabolism of lipids within the glomeruli and renal tubules. Indeed, evidence indicates that apolipoproteins have multiple functions in regulating lipid import, transport, synthesis, storage, oxidation and export, and they are important for normal physiological function. Apolipoproteins are also risk factors for several renal diseases; for example, apolipoprotein L polymorphisms induce kidney diseases. Furthermore, renal apolipoprotein gene expression is substantially regulated under various physiological and disease conditions. This review is aimed at describing recent clinical and basic studies on the major roles and functions of apolipoproteins in the kidneys.

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