The retinoblastoma protein is phosphorylated during specific phases of the cell cycle

Buchkovich, Karen; Duffy, Linda; Harlow, Ed

doi:10.1016/0092-8674(89)90508-4

Cited by 966 publications

(540 citation statements)

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“…We found that, after PHA stimulation, the amount of (Buchkovich et al, 1989;Chen et al, 1989;Mihara et al, 1989) and other studies showing variation in Rb protein levels in B and T lymphocytes, when cells entered the S-phase in response to mitogens (Martinez et al, 1993;Tereda et al, 1991). This increase in Rb protein along the cell cycle has also been detected in other cell types (Xu et al, 1991b), and is also found in this study in reactive tonsils, which show a similar pattern of staining for Rb and Ki67.…”

Section: Discussionsupporting

confidence: 65%

“…Retinoblastoma susceptibility gene (Rb) is a tumoursuppressor gene that codes for a nuclear phosphoprotein which plays a key role in cell cycle regulation (Buchkovich et al, 1989;Mihara et al, 1989;Chen et al, 1989). Although Rb protein is expressed in all the human organs examined, this expression is at heterogeneous levels which seem to be related to the growth and differentiation status of each cell type (Cordon-Cardo and Richon, 1994).…”

mentioning

confidence: 99%

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Anomalous retinoblastoma protein expression in Sternberg-Reed cells in Hodgkin's disease: a comparative study with p53 and Ki67 expression

Sánchez‐Beato

Martínez-Montero²,

Doussis-Anagnostopoulou³

et al. 1996

Br J Cancer

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 99%

Anomalous retinoblastoma protein expression in Sternberg-Reed cells in Hodgkin's disease: a comparative study with p53 and Ki67 expression

Sánchez‐Beato

Martínez-Montero²,

Doussis-Anagnostopoulou³

et al. 1996

Br J Cancer

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“…cyclin D (Sherr, 1994) and the cyclins responsible for DNA replication and mitosis (cyclins E, A and B). Thus, in contrast to other cell types like ®broblats, where pRb phosphorylation occurs throughout the cell cycle (Buchkovich et al, 1989;Chen et al, 1989;DeCaprio et al, 1989DeCaprio et al, , 1992Mihara et al, 1989) it appears that in 7TD1 cells pRb is phosphorylated predominantly by cyclin D2/CDK4. Indeed, 4 h after the addition of fresh medium, pRb became phosphorylated ( Figure 2b) concomitantly with the increase of cyclin D2 levels (Figure 3b) and the augmentation of cyclin D2/CDK4-associated kinase activity (Figure 3a).…”

Section: Dmso Abrogated Cyclin D2/cdk4 Activity and Impaired Prb Phosmentioning

confidence: 75%

Early G1 growth arrest of hybridoma B cells by DMSO involves cyclin D2 inhibition and p21[CIP1] induction

et al. 1998

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Dimethylsulfoxide (DMSO) was shown to inhibit the proliferation of several B cell lines including Raji, Daudi, and SKW6-CL4 but the mechanisms involved in this growth arrest are still unclear. We show that in 7TD1 mouse hybridoma cells a DMSO-induced reversible G 1 arrest involves inactivation of Rb kinases, cyclin D2/ CDK4 and cyclin E/CDK2. This occurs by at least three distinct mechanisms. Inhibition of cyclin D2 neosynthesis leads to a dramatic decrease of cyclinD2/CDK4 complexes. This in turn enables the redistribution of p27 [KIP1] from cyclin D2/CDK4 to cyclin E/CDK2 complexes. In addition, the simultaneous accumulation of p21 [CIP1] entails increasing association with cyclin D3/ CDK4 and cyclin E/CDK2. Thus, p21 [CIP1] and p27 [KIP1] , act in concert to inhibit cyclin E/CDK2 activity which, together with CDK4 inactivation, confers a G 1 -phase arrest.

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“…Progression through the cell cycle can be monitored by assessing levels of pRb and p27 in both their un/hypophosphorylated (pRb and p27), and hyperphosphorylated (phosphopRb and phospho-p27) states (Buchkovich et al, 1989;Vlach et al, 1997;Howard et al, 2000). Antibodies directed against total pRb or total p27 are likely to detect both the hyper-and hypo/nonphosphorylated forms of the protein (Buchkovich et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

“…Antibodies directed against total pRb or total p27 are likely to detect both the hyper-and hypo/nonphosphorylated forms of the protein (Buchkovich et al, 1989). Elevated levels of p27 induces G1 arrest (Sherr, 2000).…”

Section: Discussionmentioning

confidence: 99%

Assessing proliferation, cell-cycle arrest and apoptotic end points in human buccal punch biopsies for use as pharmacodynamic biomarkers in drug development

et al. 2005

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Easily accessible normal tissues expressing the same molecular site(s) of drug action as malignant tissue offer an enhanced potential for early proof of anticancer drug mechanism and estimation of the biologically effective dose. Studies were undertaken in healthy male volunteers to assess the tolerability of single and multiple (four in 24 h) 3 mm punch biopsies of the buccal mucosa, and to determine the feasibility of detecting and quantifying a range of proliferation, cell-cycle arrest and apoptosis markers by immunohistochemistry (IHC) for use as potential pharmacodynamic (PD) end points. The biopsy procedure was well tolerated with 100% of volunteers stating that they would undergo single (n ¼ 10) and multiple (n ¼ 12) biopsies again. Total retinoblastoma protein (pRb), phosphorylated pRb (phospho-pRb), total p27, phosphorylated p27 (phospho-p27), phosphorylated-histone H3 (phospho-HH3), p21, p53, Cyclin A, Cyclin E, Ki67 all produced good signal detection, but M30, cleaved caspase 3 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling did not. Total pRb, phospho-pRb, total p27 and phospho-p27 were quantified further in a multiple biopsy study to allow components of variability to be addressed to inform future sizing decisions on intervention studies. Neither site of biopsy within the oral cavity, nor the nominal time of biopsy had any significant impact on any of the four markers expression levels. Inter-and intrasubject coefficients of variation (CVs) that could be used to size future intervention studies for pRb, phospho-pRb, total p27 and phospho-p27 were 14, 19, 18 and 16%; and 18, 29, 25 and 19%, respectively. In conclusion, quantitation of such markers in 3 mm buccal punch biopsies would be suitable to explore as PD end points within intervention studies of drugs acting on these pathways.

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The retinoblastoma protein is phosphorylated during specific phases of the cell cycle

Cited by 966 publications

References 51 publications

Anomalous retinoblastoma protein expression in Sternberg-Reed cells in Hodgkin's disease: a comparative study with p53 and Ki67 expression

Anomalous retinoblastoma protein expression in Sternberg-Reed cells in Hodgkin's disease: a comparative study with p53 and Ki67 expression

Early G1 growth arrest of hybridoma B cells by DMSO involves cyclin D2 inhibition and p21[CIP1] induction

Assessing proliferation, cell-cycle arrest and apoptotic end points in human buccal punch biopsies for use as pharmacodynamic biomarkers in drug development

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