Disease relevance of RBL1

• p107 is a retinoblastoma protein-related phosphoprotein that, when overproduced, displays a growth inhibitory function [1].
• The p107 protein is targeted by many viral proteins, including adenovirus E1A, simian virus 40 large T antigen, and human papillomavirus type 16 E7 protein [2].
• In addition, p107 was found to associate with 62- to 65- and 50-kDa phosphoproteins in ML-1 cells, a human myeloid leukemia cell line [2].
• Interaction between human cyclin A and adenovirus E1A-associated p107 protein [3].
• Differential expression of Rb2/p130 and p107 in normal human tissues and in primary lung cancer [4].

High impact information on RBL1

• Previously known as the ultimate recipients of cdk regulatory signals, E2F4/5 and p107 act here as transducers of TGFbeta receptor signals upstream of cdk [5].
• E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression [5].
• Comparison analysis of the p107 protein sequence reveals a major region of RB homology extending over 564 residues [6].
• Molecular cloning, chromosomal mapping, and expression of the cDNA for p107, a retinoblastoma gene product-related protein [6].
• Thus, these two proteins display similarities of structure that may, at least in part, explain their known functional similarities and suggest a generic function for p107 in cell cycle regulation [6].

Chemical compound and disease context of RBL1

• We found a decrease in serine phosphorylation of the retinoblastoma protein Rb (p107) after incubation with GST-D5 [7].
• Furthermore, the S phase inhibitory response to cisplatin is augmented by the ectopic expression of wild type p107, although it is diminished by the adenovirus E1A oncoprotein, which counteracts the pocket protein functions [8].
• Moreover, p107, but not pRb, repressed transcription from other promoters including fibronectin, herpes virus thymidine kinase, and a synthetic promoter containing a SV40 repeat activator motif upstream from the adenovirus major late-promoter TATA box [9].
• We speculate that down-regulation of hPRB may predict for poorly differentiated endometrial cancers that do not respond to progestin therapy [10].
• We examined the effects of cyclic AMP (cAMP) on the growth and differentiation of RAO 188 cells, a cultured cell line derived from a retinoblastoma-like tumor induced in an inbred rat by intravitreous inoculation with human adenovirus serotype 12 [11].

Biological context of RBL1

• Our results show that p107 phosphorylation begins in mid G1 and proceeds through late G1 and S and that cyclin D-associated kinase(s) contributes to this process [1].
• Its activity is controlled by the cell cycle regulators pRB, p107, and p130 [12].
• Coordinated interactions between cyclin-dependent kinases (Cdks), their target "pocket proteins" (the retinoblastoma protein [pRB], p107, and p130), the pocket protein binding E2F-DP complexes, and the Cdk inhibitors regulate orderly cell cycle progression [13].
• In contrast, pRb-related proteins p107 and p130, which also decrease cyclin E-kinase activity, do not cause an accumulation of p27(KIP1) and induce senescence poorly [14].
• The retinoblastoma (pRb), p107, and p130 pocket proteins bind to the E2F transcription factors to control gene expression [15].

Anatomical context of RBL1

• Here, we show that pRb2/p130 and Rb1/p105, but not p107, interact with PAI-2 in both the cytoplasm and nucleus of normal primary human corneal and conjunctival epithelial cells [16].
• We have determined how the phosphorylation of the retinoblastoma family (pRb, p107, and p130) is governed in individual cell cycle phases of Daudi B-cells during cell cycle exit triggered by alpha-interferon (alpha-IFN). alpha-IFN causes dephosphorylation of pRb and loss of p130 phosphorylated Form 3 [17].
• We found that during in vitro differentiation of human HaCaT keratinocytes, pRb, p107 and p130 are sequentially expressed, in contrast to the co-expression observed during cell cycle progression in the same cells [18].
• Terminally differentiated cells, such as neurons and skeletal muscle, showed high expression levels for Rb2/p130, whereas p107 was expressed at higher levels in other cell types such as epithelia of the breast and prostate [4].
• p107 is active in the nucleolus in non-dividing human granulosa lutein cells [19].

Associations of RBL1 with chemical compounds

• In model p107 spacer region peptides, phosphorylation of S640 by cyclin D1/Cdk4 is strictly dependent upon an intact RXL motif, but phosphorylation of this site in the absence of an RXL motif can be partially restored by replacement of S643 by arginine [20].
• Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)) [21].
• The cancer preventive flavonoid silibinin causes hypophosphorylation of Rb/p107 and Rb2/p130 via modulation of cell cycle regulators in human prostate carcinoma DU145 cells [22].
• Levels of p185HER2 and the extent of its tyrosine phosphorylation were similar in all transfectant clones, as were levels of pRb1 and p107 [23].
• However, the co-transfection of pRb and p107 induced the expression of early differentiation markers (keratin k10) and triple transfectants pRb+p107+p130 expressed markers representative of later stages of epidermal differentiation (involucrin) [18].

Physical interactions of RBL1

• HDAC1 interacts with p107 and Rb through an "LXCXE"-like motif, similar to that used by viral transforming proteins to bind and inactivate pocket proteins [24].
• Further, a role for this amino-terminal region in growth suppression was uncovered by using p107 mutants unable to bind E2F [25].
• Recent genetic evidence indicates a requirement for cyclin D1/Cdk4 complexes in p107 inactivation [20].
• In a first series of experiments, we showed that pRb2/p130 and p107 are not evenly distributed within the nucleus and that cell cycle-dependent binding with E2F4 changes also as a function of their subnuclear localization [26].
• Dual cyclin-binding domains are required for p107 to function as a kinase inhibitor [27].

Enzymatic interactions of RBL1

• In contrast, only the cyclin A-cdk complexes phosphorylated the Rb-related p107 protein in vitro [28].
• A conserved site at Ser842 in the related pocket protein p107 is also preferentially phosphorylated by cdk4/D1 [29].

Regulatory relationships of RBL1

• p130 and p107 use a conserved domain to inhibit cellular cyclin-dependent kinase activity [25].
• The p107 tumor suppressor induces stable E2F DNA binding to repress target promoters [30].
• In this study we examined the functions of B-Myb required to overcome G1 arrest in Saos-2 cells induced by the retinoblastoma-related p107 protein [31].
• Evidence that Cdk4/6 activity is inhibited by p16(INK4A) in most pRB(-) cells suggests that p107 and p130 may be underphosphorylated and remain associated with E2Fs during G(1)-S progression in cells that lack pRB [32].
• Experiments utilizing Gal4-RB and Gal4-p107 chimeric constructs demonstrated that either RB or p107 could directly repress TGF-beta induction of p15(INK4B) gene when tethered to p15(INK4B) promoter through Gal4 DNA binding sites [33].

Other interactions of RBL1

• E2F family members are functionally regulated, in part, by complex formation with one or more members of the nuclear pocket protein family, RB, p107, and p130 [34].
• Regulation of the retinoblastoma protein-related protein p107 by G1 cyclin-associated kinases [1].
• Indeed, we find that the viral transforming protein E1A competes with HDAC1 for p107 interaction [24].
• However, in contrast to OVCAR8 cells, induction of p130 and p107 appears to play an important role in the inhibition of growth of C33A cells by MIS [35].
• The growth suppressor activities of the RB and p107 products are believed to be mediated by the reversible binding of a heterogeneous family of cellular proteins to a conserved T/E1A pocket domain that is present within both proteins [36].

Analytical, diagnostic and therapeutic context of RBL1

• Using genome-wide chromatin immunoprecipitation, we show that there are distinct classes of genes directly regulated by unique combinations of E2F4, p107, and p130, including a group of genes specifically regulated in cycling cells [37].
• Immunofluorescence studies on skin sections revealed the presence of pRb and p107 in basal and suprabasal cell layers, whilst p130 is restricted to cells already committed to differentiation in the suprabasal compartments [18].
• Immunocytochemistry shows that these proteins are expressed in almost all GLC but have different sub-cellular distribution: p107 is concentrated in nucleoli, while p130 and E2F-4 show relatively even nuclear and cytoplasmic distributions [19].
• Site-directed mutagenesis of these E2F sites revealed that although both sites were important for p107 promoter activity, mutation on the proximal, initiation site copy of the E2F site showed a stronger effect [38].
• Western blot analysis revealed diminution of cyclin D1, Rb, and p107 protein levels after flavopiridol exposure [39].

References