Proliferative Suppression by CDK4/6 Inhibition: Complex Function of the Retinoblastoma Pathway in Liver Tissue and Hepatoma Cells

Rivadeneira, Dayana B.; Mayhew, Christopher N.; Thangavel, Chellappagounder; Sotillo, Elena; Reed, Christopher A.; Graña, Xavier; Knudsen, Erik S.

doi:10.1053/j.gastro.2010.01.007

Cited by 111 publications

(94 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Accordingly, Huh7 and HepG2 cells treated with PD-0332991, a potent inhibitor of these kinases, arrested the cells in G 1 phase. 34 Here we demonstrate that miR-33 targets CCND1 and CDK6 and regulates hepatocyte proliferation. In addition to CCND1 and CDK6, it has previously been reported that miR-33 also targets p53.…”

Section: Discussionmentioning

confidence: 99%

Mir-33 regulates cell proliferation and cell cycle progression

et al. 2012

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Mir-33 regulates cell proliferation and cell cycle progression

et al. 2012

View full text Add to dashboard Cite

“…1 The G1/S is a crucial cell cycle checkpoint, which is controlled by 2 cell cycle kinases, CDK4/6-cyclin D1 and CDK2-cyclin E, and the transcription complex that includes Rb and E2F. 44 Rb phosphorylation by CDK4/6 and CDK2 dissociates the E2 promoter-binding protein dimerization partners (E2F) from the pRb/E2F complex, and dissociated E2F induces transcription of cyclin E1, amplifying the G1-to S-phase switch, and being required for DNA replication. 45 Consistent with our studies, we show that the expression of CDK4/cyclin D1, CDK2/cyclin E and phosphorylation of Rb were increased parralel with PKM2, indicating cell cycle activation.…”

Section: Discussionmentioning

confidence: 99%

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

et al. 2015

View full text Add to dashboard Cite

Department of Stomatology; Affiliated Hospital of Nantong University, Nantong; Nantong University; 226001, Nantong, Jiangsu, PR China y These authors equally contributed to this work, and should be considered as joint first authors.Keywords: astrocyte proliferation, b-catenin, p27, PKM2, spinal cord injuryAbbreviations: CNS, Central nervous system; CDKs, cyclin-dependent kinases; CAK, CDK activating kinase; E2F, E2 promoter-binding protein dimerization partners; GFAP, Glial fibrillary acidic protein; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; NeuN, Neuronal nuclei; PCNA, Proliferating cell nuclear antigen; PEP, phosphoenolpyruvate; PK, Pyruvate kinase; PKM2, pyruvate kinase M2; pRb, protein retinoblastoma; SCI, Spinal cord injury; EGFR, Epidermal growth factor receptor.Aberrant functionality of the cell cycle has been implicated in the pathology of traumatic SCI. Although it has been reported that the expressions of various cell cycle related proteins were altered significantly following SCI, detailed information on the subject remains largely unclear. The embryonic pyruvate kinase M2 (PKM2) is an important metabolic kinase in aerobic glycolysis or the warburg effect, however, its functions in central nervous system (CNS) injury remains elusive. Here we demonstrate that PKM2 was not only significantly upregulated by western blot and immunohistochemistry but certain traumatic stimuli also induced translocation of PKM2 into the nucleus in astrocytes following spinal cord injury (SCI). Furthermore, the expression levels and localization of p-b-catenin, p27, cyclin D1 and PCNA were correlated with PKM2 after SCI. In vitro, we also found that PKM2 co-immunoprecipitation with p-b-catenin and p27 respectively. Knockdown of PKM2 apparently decreased the level of PCNA, cyclinD1, p27 in primary astrocyte cells. Taken together, our findings indicate that nuclear translocation of PKM2 promotes astrocytes proliferation after SCI through modulating cell cycle signaling. These discoveries firstly uncovered the role of PKM2 in spinal cord injury and provided a potential therapeutic target for CNS injury and repair.

show abstract

“…Some activity was seen also in other Rb-deficient cells owing to this mechanism [Rivadeneira et al 2010].…”

Section: Cell Cycle and Endocrine Resistancementioning

confidence: 99%

Progress with palbociclib in breast cancer: latest evidence and clinical considerations

et al. 2016

View full text Add to dashboard Cite

Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HRpositive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer.

show abstract

Proliferative Suppression by CDK4/6 Inhibition: Complex Function of the Retinoblastoma Pathway in Liver Tissue and Hepatoma Cells

Cited by 111 publications

References 29 publications

Mir-33 regulates cell proliferation and cell cycle progression

Mir-33 regulates cell proliferation and cell cycle progression

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

Progress with palbociclib in breast cancer: latest evidence and clinical considerations

Contact Info

Product

Resources

About