Point Mutational Inactivation of the Retinoblastoma Antioncogene

Horowitz, Jordan M.; Yandell, David W.; Park, Sang-Ho; Canning, Susan; Whyte, Peter; Buchkovich, Karen; Harlow, Ed; Weinberg, Robert A.; Dryja, Thaddeus P.

doi:10.1126/science.2521957

Cited by 385 publications

(163 citation statements)

References 30 publications

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“…GAL4-Rb mutants that only contain either domain A or B of the pocket or only the C-terminal region were signi®cantly reduced in their ability to associate with TAF II 250. The introduction of two naturally occurring mutations, C706F and J82 (D703 ± 737) (Horowitz et al, 1989), into the pocket region of Rb partially reduced the binding to TAF II 250 (data not shown). However, domain B plus the C-terminal region (649 ± 928) bound only weakly to TAF II 250 (data not shown).…”

Section: Mapping Of the Domains In Rb Important For Binding Taf II 25mentioning

confidence: 92%

Rb interacts with TAFII250/TFIID through multiple domains

Shao

Siegert

Ruppert³

et al. 1997

Oncogene

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The retinoblastoma tumor suppressor gene product (Rb) binds directly to the largest TFIID subunit, TATAbinding protein associated factor TAF II 250, ®rst identi®ed as the cell cycle regulatory protein CCG1. Here we map the domains in Rb and TAF II 250 important for their interaction in vitro and in vivo. Both the amino terminus and the large pocket of Rb are able to associate independently with TAF II 250. The binding domain(s) within the large pocket are distinct from the viral oncoprotein and E2F binding region since certain pocket mutations, which abolish E1A binding, do not abolish TAF II 250 binding. Consistent with the large pocket of Rb binding to TAF II 250, the large pocket domains of both p107 and p130 are able to bind to TAF II 250 in vivo. We also demonstrate that at least two regions of TAF II 250 are able to bind to the large pocket of Rb independently whereas the amino terminus of Rb binds to a distinct domain in TAF II 250. We further demonstrate that Rb can bind to TFIID in vitro, presumably in part through an interaction with TAF II 250. Our results suggest a complex interaction between Rb and TAF II 250 and imply that TAF II 250, TFIID, and potentially other basal transcription factors are targets for regulation by Rb and Rb-related proteins.

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Section: Mapping Of the Domains In Rb Important For Binding Taf II 25mentioning

confidence: 92%

Rb interacts with TAFII250/TFIID through multiple domains

Shao

Siegert

Ruppert³

et al. 1997

Oncogene

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“…In addition, we analyzed two well characterized pRB-mutants, DELTA exon21 and C706F, presumed to represent null alleles with complete loss of activity (Horowitz et al, 1989;Kratzke et al, 1992; Saijo et al, 994) and another, R661W, with partial loss of function and associated with low disease penetrance and expressivity in nine families (Otterson et al, 1997).…”

Section: Biological Functioning Of Prb Delta Aa831-928mentioning

confidence: 99%

“…This is supported by antibody specific for the underphophorylated form of pRB (Zarkowska et al, 1997), revealing that the relative amount of the underphosphorylated form is far higher and may account for the entire pool of pRB DELTA AA831-928 expressed in the transfected cells. Defective phosphorylation has been noticed with other oncogenic pRB-mutants and correlates with loss of wt function in pRB (Horowitz et al, 1989;Kaye et al, 1990;Templeton et al, 1991). …”

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confidence: 99%

A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity

et al. 2005

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Hereditary predisposition to retinoblastoma is caused by germ line mutations in the RB1 gene. Genetic counseling of affected individuals and accurate risk prediction for their families requires identification of the disease causing mutation. Furthermore, the nature of a mutation can determine genetic penetrance, disease presentation and prognosis. We describe, and functionally characterize here, a novel mutant allele of RB1 present in the germ line of a patient with sporadic bilateral retinoblastoma. The mutation generates an operational splice acceptor site resulting in a predicted protein product with loss of 81 amino acids from its carboxy terminus. We demonstrate that the aberrantly spliced transcript is present in substantial amounts in peripheral blood of the patient and present evidence that the predicted protein product displays partial loss of activity reflecting in degree and presentation that of the partially penetrant RB1 missense mutant R661W. This infers that disease with reduced expressivity and incomplete penetrance may arise in individuals that carry the mutation and predicts such presentation for similar mutations with found in sporadic cases in the past. © 2004 Wiley-Liss, Inc.KEY WORDS: retinoblastoma; reduced expressivity; penetrance; splicing; RB1; pRB INTRODUCTIONRetinoblastoma, a childhood tumor of the eye, is caused by inactivation in the developing human retina of both alleles of the RB1 tumor suppressor gene (MIM# 180200) (reviewed in DiCiommo et al., 2000). In hereditary retinoblastoma (accounting for roughly 50% of cases) one RB1 allele is mutated in the germ line as either a novel or an inherited mutation. In this instance disease usually presents at an early age, with multiple tumor foci in both eyes, a high incidence of disease recurrence, increased lifetime risk for secondary malignancies and transmission to kindred with a penetrance of greater 95%. In its nonhereditary form mutational inactivation of both RB1 alleles DOI: 10.1002/humu.9305 2 Sánchez-Sánchez et al.arises from somatic events in a single retinal cell. Here disease presentation is far milder disease featuring late onset, single tumor foci in one eye only and absence of recurrence and secondary tumor development. In rare instance hereditary retinoblastoma can present in a form reminiscent to the non-hereditary disease (reduced expressivity), and often in this instance shows reduced penetrance in kindred (low penetrance).The product of the human RB1 gene (p110RB/pRB) is a nuclear phospho-protein composed of 928 amino acids. Through interacting with cellular proteins pRB influences cell proliferation, but also other types of cell behavior (reviewed in Kaelin, 1999;Zheng and Lee, 2001). Most noted is the function of pRB to control gene transcription via E2F (reviewed in Harbour and Dean, 2000;Stevens and La Thangue, 2003). Through association with specific members of this transcription factor family pRB represses genes required for cell cycle progression and proliferation, and by attracting additional chromatin modifyin...

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“…cyclin dependent kinase (CDK) complex. [3][4][5][6][7] Inactivation of the Rb gene has been implicated in the pathogenesis of a wide variety of human solid tumors, including osteosarcomas and Materials and methods soft tissue sarcomas, 1,[8][9][10][11][12][13][14][15] carcinomas of the breast, [16][17][18] lung, 19-23 prostate 24 and bladder, 25 and of course retinoblasSamples tomas. [26][27][28] High level of expression of the Rb protein or Rb gene amplification has also been reported in some Cells were collected from 40 Japanese ATL patients before tumors.…”

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confidence: 99%