Retinoblastoma Protein Paralogs and Tumor Suppression

Flores, Mauricio A.; Goodrich, David W.

doi:10.3389/fgene.2022.818719

Cited by 8 publications

(5 citation statements)

References 139 publications

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“…As the Rb protein family also includes 2 more additional members, RBL1 and RBL2, which may have overlapping functions with Rb (14), we checked whether there might be analogous correlation of RBL1 and RBL2 with the survival outcome of ovarian cancer patients. In contrast to Rb1 gene, we did not detect the same association for RBL1 or RBL2 genes, underlining Rb1 as a major factor in this relation ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Rb contains at least two pockets in its structure (a major cell cycle regulation pocket with A and B domains; second cleft pocket in domain B including the LxCxE binding motif). Consequently, Rb pocket regions interact with numerous adaptor proteins able to selectively control cell cycle and survival events (14,15). The functional consequences of these interactions in immune cells at various differentiation status are still poorly understood and to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Targeting LxCxE cleft pocket of retinoblastoma protein in M2 macrophages inhibits ovarian cancer progression

Tcyganov,

Kwak,

Yang

et al. 2024

Preprint

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Ovarian cancer remains a major health threat with limited treatment options available. It is characterized by immunosuppressive tumor microenvironment (TME) maintained by tumor-associated macrophages (TAMs) hindering anti-tumor responses and immunotherapy efficacy. Here we show that targeting retinoblastoma protein (Rb) by disruption of its LxCxE cleft pocket, causes cell death in TAMs by induction of ER stress, p53 and mitochondria-related cell death pathways. A reduction of pro-tumor Rbhigh M2-type macrophages from TME in vivo enhanced T cell infiltration and inhibited cancer progression. We demonstrate an increased Rb expression in TAMs in women with ovarian cancer is associated with poorer prognosis. Ex vivo, we show analogous cell death induction by therapeutic Rb targeting in TAMs in post-surgery ascites from ovarian cancer patients. Overall, our data elucidates therapeutic targeting of the Rb LxCxE cleft pocket as a novel promising approach for ovarian cancer treatment through depletion of TAMs and re-shaping TME immune landscape.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting LxCxE cleft pocket of retinoblastoma protein in M2 macrophages inhibits ovarian cancer progression

Tcyganov,

Kwak,

Yang

et al. 2024

Preprint

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“…As is known, the human retinoblastoma susceptibility gene (RB1), a tumor-suppressor gene, is mutated at various frequencies in a wide range of cancers. The RB1 protein (pRB) plays important roles in different molecular processes, such as gene transcription, DNA replication, and DNA repair [ 27 ]. IOX2, a well-characterized and selective inhibitor of the HIF prolyl-hydroxylases, has been reported to exert an anti-proliferative in human breast cancer cell lines [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

DBDNMF: A Dual Branch Deep Neural Matrix Factorization method for drug response prediction

Liu,

Wang,

et al. 2024

PLoS Comput Biol

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Anti-cancer response of cell lines to drugs is in urgent need for individualized precision medical decision-making in the era of precision medicine. Measurements with wet-experiments is time-consuming and expensive and it is almost impossible for wide ranges of application. The design of computational models that can precisely predict the responses between drugs and cell lines could provide a credible reference for further research. Existing methods of response prediction based on matrix factorization or neural networks have revealed that both linear or nonlinear latent characteristics are applicable and effective for the precise prediction of drug responses. However, the majority of them consider only linear or nonlinear relationships for drug response prediction. Herein, we propose a Dual Branch Deep Neural Matrix Factorization (DBDNMF) method to address the above-mentioned issues. DBDNMF learns the latent representation of drugs and cell lines through flexible inputs and reconstructs the partially observed matrix through a series of hidden neural network layers. Experimental results on the datasets of Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) show that the accuracy of drug prediction exceeds state-of-the-art drug response prediction algorithms, demonstrating its reliability and stability. The hierarchical clustering results show that drugs with similar response levels tend to target similar signaling pathway, and cell lines coming from the same tissue subtype tend to share the same pattern of response, which are consistent with previously published studies.

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“…In G1, the sequential activation of cdk4/6-cyclin D and cdk2-cyclin A/E complexes ensures complete phosphorylation and inactivation of the Rb family of transcriptional repressors, thereby activating E2F transcription factors and inducing the expression of their proliferative target genes ( 1 ). Many human tumors display a defect in Rb function, e.g., loss of Rb or amplification of specific cyclin or cdk genes ( 2 – 4 ). The cell cycle is initiated by the activation of cdk4/6 by the formation of cyclin D-cdk4/6 complexes ( 1 ).…”

Section: Introductionmentioning

confidence: 99%

The SREBP-dependent regulation of cyclin D1 coordinates cell proliferation and lipid synthesis

2022

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The sterol regulatory-element binding protein (SREBP) family of transcription factors regulates cholesterol, fatty acid, and triglyceride synthesis and metabolism. However, they are also targeted by the ubiquitin ligase Fbw7, a major tumor suppressor, suggesting that they could regulate cell growth. Indeed, enhanced lipid synthesis is a hallmark of many human tumors. Thus, the SREBP pathway has recently emerged as a potential target for cancer therapy. We have previously demonstrated that one of these transcription factors, SREBP1, is stabilized and remains associated with target promoters during mitosis, suggesting that the expression of these target genes could be important as cells enter G1 and transcription is restored. Activation of cyclin D-cdk4/6 complexes is critical for the phosphorylation and inactivation of the retinoblastoma protein (Rb) family of transcriptional repressors and progression through the G1 phase of the cell cycle. Importantly, the cyclin D-cdk4/6-Rb regulatory axis is frequently dysregulated in human cancer. In the current manuscript, we demonstrate that SREBP1 activates the expression of cyclin D1, a coactivator of cdk4 and cdk6, by binding to an E-box in the cyclin D1 promoter. Consequently, inactivation of SREBP1 in human liver and breast cancer cell lines reduces the expression of cyclin D1 and attenuates Rb phosphorylation. Rb phosphorylation in these cells can be rescued by restoring cyclin D1 expression. On the other hand, expression of active SREBP1 induced the expression of cyclin D1 and increased the phosphorylation of Rb in a manner dependent on cyclin D1 and cdk4/6 activity. Inactivation of SREBP1 resulted in reduced expression of cyclin D1, attenuated phosphorylation of Rb, and reduced proliferation. Inactivation of SREBP1 also reduced the insulin-dependent regulation of the cyclin D1 gene. At the same time, SREBP1 is known to play an important role in supporting lipid synthesis in cancer cells. Thus, we propose that the SREBP1-dependent regulation of cyclin D1 coordinates cell proliferation with the enhanced lipid synthesis required to support cell growth.

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Retinoblastoma Protein Paralogs and Tumor Suppression

Cited by 8 publications

References 139 publications

Targeting LxCxE cleft pocket of retinoblastoma protein in M2 macrophages inhibits ovarian cancer progression

Targeting LxCxE cleft pocket of retinoblastoma protein in M2 macrophages inhibits ovarian cancer progression

DBDNMF: A Dual Branch Deep Neural Matrix Factorization method for drug response prediction

The SREBP-dependent regulation of cyclin D1 coordinates cell proliferation and lipid synthesis

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