Physical interaction of the retinoblastoma protein with human D cyclins

Dowdy, Steven F.; Hinds, Philip W.; Louie, Kenway; Reed, Steven I.; Arnold, Andrew; Weinberg, Robert A.

doi:10.1016/0092-8674(93)90137-f

Cited by 722 publications

(601 citation statements)

References 77 publications

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“…Together, these data provide strong evidence for the model that B subunits of PP2A act as targeting devices that recruit cellular substrates of PP2A to the PP2A catalytic subunit. This situation is reminiscent of the interaction of D type cyclins with pRb, in which the regulatory cyclin component can also target the catalytic cdk component to its substrate (Dowdy et al, 1993;Ewen et al, 1993). In most cases, such interactions between enzymes and substrates are unstable and transient in nature.…”

Section: Discussionmentioning

confidence: 99%

“…Not only pRb, but also p107 can be phosphorylated and thereby inactivated as a growth suppressor by the cyclin D1/ cdk4 kinase complex. In addition, pRb, but not p107, is thought to be a substrate for cyclin A/cdk2 and cyclin E/cdk2 (Hinds et al, 1992;Dowdy et al, 1993;Ewen et al, 1993;Beijersbergen et al, 1995). It is somewhat enigmatic that even though p107 and p130 do not appear to be phosphorylated by cyclin A/cdk2 and cyclin E/cdk2, both pocket proteins can form stable complexes with cyclin A/cdk2 and E/cdk2 through a domain within the pocket called the spacer (Lees et al, 1992;Shirodkar et al, 1992;Li et al, 1993a;Zhu et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Functional interaction between a novel protein phosphatase 2A regulatory subunit, PR59, and the retinoblastoma-related p107 protein

1999

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The proteins of the retinoblastoma family are potent inhibitors of cell cycle progression. It is well documented that their growth-inhibitory activity can be abolished by phosphorylation on serine and threonine residues by cyclin dependent kinases. In contrast, very little is known about the dephosphorylation of retinoblastoma-family proteins. We report here the isolation, by virtue of its ability to associate with p107, of a novel Protein Phosphatase 2A (PP2A) regulatory subunit, named PR59. PR59 shares sequence homology with a known regulatory subunit of PP2A, PR72, but di ers from PR72 in its expression pattern and its functional properties. We show that PR59 co-immunoprecipitates with the PP2A catalytic subunit, indicating that PR59 is a genuine component of PP2A holo-enzymes. In vivo, PR59 associates speci®cally with p107, but not with pRb. Elevated expression of PR59 results in dephosphorylation of p107, but not of pRb, and inhibits cell proliferation by causing cells to accumulate in G1. These data support a model in which the distinct PP2A regulatory subunits act to target the PP2A catalytic subunit to speci®c substrates and suggest a role for PP2A in regulation of p107.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional interaction between a novel protein phosphatase 2A regulatory subunit, PR59, and the retinoblastoma-related p107 protein

1999

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“…As interaction of Rb with other proteins has been demonstrated in a number of contexts (Chellappan et al, 1991;Dowdy et al, 1993;Gu et al, 1993;Hagemeier et al, 1993;Whyte et al, 1988), we hypothesized that a speci®c interaction might occur in F5-5 cultures upon activin treatment. F5-5 cells were cultured with or without activin and immunoprecipitated with rabbit anti-Rb antibodies or rabbit anti-CDK4 antibodies as control.…”

Section: Ectopic Expression Of Goosecoid (Gsc) In the Erythroblast Cementioning

confidence: 99%

GOOSECOID inhibits erythrocyte differentiation by competing with Rb for PU.1 binding in murine cells

Konishi¹,

Tominaga²,

Watanabe³

et al. 1999

Oncogene

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“…Cyclin D1 and cyclin D3 are the major forms expressed in rat intestinal epithelial cells (Ko et al, 1995). The only known substrate for the activated Cdk4 is the retinoblastoma protein, pRB (Matsushime et al, 1992;Dowdy et al, 1993;Kato et al, 1993). In its hypophosphorylated form, pRB can bind and inhibit transcription factors, including heterodimers of the E2F and DP families of proteins (Farnham et al, 1993;Flemington et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Sakai

et al. 1998

Oncogene

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Transforming growth factor-beta 1 (TGF-b1) arrests intestinal epithelial cells (RIE-1 and IEC-6) in the G1 phase of the cell cycle and inhibits cyclin D1 expression. This report describes experiments designed to elucidate the mechanism of cyclin D1 inhibition and to determine whether inhibition of cyclin D1 expression is the cause, rather than the result, of TGF-b1-mediated cell cycle arrest. TGF-b1 inhibition of IEC-6 cell proliferation was associated with a decrease in the abundance of cyclin D1/Cdk4 complexes and a corresponding decrease in Cdk4-dependent phosphorylation of the retinoblastoma protein. Metabolic labeling studies indicated that TGFb1 inhibited cyclin D1 synthesis without altering the rate of cyclin D1 protein degradation. Cyclin D1 antisense oligonucleotides blocked serum-stimulated induction of cyclin D1 and DNA synthesis, whereas cyclin D1 sense oligonucleotides had no e ect. RIE-1 cells were engineered to overexpress human cyclin D1 under the control of a tetracycline-repressible promoter. These cells entered S phase in the presence of TGF-b1 only when human cyclin D1 was derepressed by the withdrawal of tetracycline. These data indicate that TGF-b1 inhibits the synthesis of cyclin D1 in gut epithelial cells and that this inhibition is the cause, rather than the result, of TGF-b1-mediated arrest of intestinal epithelial cell proliferation.

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Physical interaction of the retinoblastoma protein with human D cyclins

Cited by 722 publications

References 77 publications

Functional interaction between a novel protein phosphatase 2A regulatory subunit, PR59, and the retinoblastoma-related p107 protein

Functional interaction between a novel protein phosphatase 2A regulatory subunit, PR59, and the retinoblastoma-related p107 protein

GOOSECOID inhibits erythrocyte differentiation by competing with Rb for PU.1 binding in murine cells

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

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