Understanding Retinoblastoma Post-Translational Regulation for the Design of Targeted Cancer Therapies

Abstract

The retinoblastoma protein (Rb1) is a prototypical tumor suppressor protein whose role was described more than 40 years ago. Together with p107 (also known as RBL1) and p130 (also known as RBL2), the Rb1 belongs to a family of structurally and functionally similar proteins that inhibits cell cycle progression. Given the central role of Rb1 in regulating proliferation, its expression or function is altered in most types of cancer. One of the mechanisms underlying Rb-mediated cell cycle inhibition is the binding and repression of E2F transcription factors, and these processes are dependent on Rb1 phosphorylation status. However, recent work shows that Rb1 is a convergent point of many pathways and thus the regulation of its function through post-translational modifications is more complex than initially expected. Moreover, depending on the context, downstream signaling can be both E2F-dependent and -independent. This review seeks to summarize the most recent research on Rb1 function and regulation and discuss potential avenues for the design of novel cancer therapies.

Arbidol inhibits human esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase

“…Phosphorylation of residues within the central pocket and c-terminal domains of RB1 (S249, T252, S356, S373, S608, S612, S780, S788, S795, S807, S811, T821, and S826) have been extensively studied. RB1 S249 is phosphorylated by CDK2, RB1 S807 and RB1 T826 is phosphorylated by CDKs to promote cell cycle progression ( Janostiak et al, 2022 ). Therefore, to verify that Arbidol triggers the G1-phase blockade independent of the CDKs/RB signaling pathway, phosphorylated RB1 (S204, S807, and T826) abundance was measured by western blot in cells after Arbidol treatment.…”

Zebrafish as an Orthotopic Tumor Model for Retinoblastoma Mimicking Routes of Human Metastasis

“…However, within the injections of one cell line we have observed a high variability of the fluorescence intensity on the days post injection from one fish to another, which limits the zebrafish model’s use in drug testing. Janostiak et al described in a review in 2022 [ 28 ] the high complexity of the regulation of the function of the RB1 protein. This complex regulation of RB1 function includes E2F-dependent and E2F-independent signaling and also post-translational modifications of RB1 by phosphorylation, acetylation and methylation and many further regulatory factors.…”

Population-enriched innate immune variants may identify candidate gene targets at the intersection of cancer and cardio-metabolic disease

“…Retinoblastoma (RB1) was one of the first tumor suppressors to be identified. Alterations in the expression and sequence of the RB1 gene have been implicated in several cancers besides retinoblastoma where they were originally characterized (reviewed in 391 ). More than 40 years of extensive research indicates that regulation of and by RB1 is highly complex, linked with multiple signaling pathways, and varies with context.…”

“…It is in this extra-exonic portion of the non-canonical 110 aa RB1 isoform that the Leu99Ser population-enriched variant, which introduces a potential phosphorylation site, is found. In spite of the high number of aa residues (n ≥ 105) in the canonical RB1 protein that are known to be post-translationally modified, within the aa 501-565 residue range that overlaps with the first 65 residues of the 110 aa isoforms, only two potential ubiquitination sites have been identified in the vicinity of aa 550) ( 391 ).…”