The membrane-associated form of cyclin D1 enhances cellular invasion

Abstract The essential G1-cyclin, CCND1, is a collaborative nuclear oncogene that is frequently overexpressed in cancer. D-type cyclins bind and activate CDK4 and CDK6 thereby contributing to G1–S cell-cycle progression. In addition to the nucleus, herein cyclin D1 was also located in the cytoplasmic membrane. In contrast with the nuclear-localized form of cyclin D1 (cyclin D1NL), the cytoplasmic membrane-localized form of cyclin D1 (cyclin D1MEM) induced transwell migration and the velocity of cellular migration. The cyclin D1MEM was sufficient to induce G1–S cell-cycle progression, cellular proliferation, and colony formation. The cyclin D1MEM was sufficient to induce phosphorylation of the serine threonine kinase Akt (Ser473) and augmented extranuclear localized 17β-estradiol dendrimer conjugate (EDC)-mediated phosphorylation of Akt (Ser473). These studies suggest distinct subcellular compartments of cell cycle proteins may convey distinct functions.

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SAT-LB135 A Novel Cytoplasmic Membrane Estrogen-Mediated Biogenic Signaling Pathway

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2002 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Richard G Pestell

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Estrogen Receptor ◽

Cyclin D1 ◽

Signaling Pathway ◽

Cell Cycle Progression ◽

Cytoplasmic Membrane ◽

Cycle Progression ◽

17Β Estradiol ◽

Localized Form

Abstract The estrogen receptor α (ERα) is known to convey both genomic and extra-genomic activities. The extra-nuclear estrogen signaling pathway is thought to involve a membrane-associated estrogen receptor (ERα), which activates PI3-kinase and Akt signaling. Maximal activation of Akt requires S473 phosphorylation. The essential G1-cyclin, CCND1, is a collaborative nuclear oncogene that is frequently overexpressed in cancer. D-type cyclins bind and activate CDK4/6, contributing to G1-S cell-cycle progression. Herein, cyclin D1 was shown to be located in the cytoplasmic membrane of patients with inflammatory breast cancer, human diploid fibroblasts and cancer cell lines (breast, prostate). The extra-nuclear vs. nuclear E2-induced signaling pathways can be distinguished using 17β-estradiol linked to a dendrimer conjugate (EDC), which excludes estradiol from the nucleus. In contrast with the nuclear-localized form of cyclin D1 (cyclin D1NL), the cytoplasmic membrane-localized form of cyclin D1 (cyclin D1CML) was sufficient to induce phosphorylation of the serine threonine kinase Akt (Ser473) and augmented extra-nuclear localized 17β-estradiol dendrimer conjugate (EDC)-mediated phosphorylation of Akt (Ser473). Cyclin D1CML was sufficient to induce G1-S cell-cycle progression, cellular proliferation, colony formation. In contrast with cyclin D1NL, the cyclin D1CML induced transwell migration and the velocity of cellular migration. Together these studies suggest distinct subcellular compartments of cell cycle proteins may convey distinct functions. The major adjuvant therapy for the ~70% of ERα expressing human breast cancer involves anti-estrogen therapy and the ERα/PI3K/Akt complex pathway is hyperactivated in aggressive breast tumors. The non-genomic actions of E2/ERα, mediated via cyclin D1CML may provide an important additional target. References. 1. 2. Casimiro MC et al Mol Endocrinol. 2013;27(9):1415-28. Di Sante, G, Expert Rev Anticancer Ther. 2019 Jun 20:1-19.

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Inhibition of Cyclin D1 Kinase Activity Is Associated with E2F-Mediated Inhibition of Cyclin D1 Promoter Activity through E2F and Sp1

Molecular and Cellular Biology ◽

10.1128/mcb.18.6.3212 ◽

1998 ◽

Vol 18 (6) ◽

pp. 3212-3222 ◽

Cited By ~ 112

Author(s):

Genichi Watanabe ◽

Chris Albanese ◽

Richard J. Lee ◽

Anne Reutens ◽

Gino Vairo ◽

...

Keyword(s):

Cell Cycle ◽

Cyclin D1 ◽

Promoter Activity ◽

Cell Cycle Progression ◽

Cellular Proliferation ◽

Kinase Activity ◽

D1 Protein ◽

Binding Domain ◽

Cycle Progression ◽

Amino Terminal

ABSTRACT 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. The cyclin D1 gene encodes a regulatory subunit of the Cdk holoenzymes, which phosphorylate the tumor suppressor pRB, leading to the release of free E2F-1. Overexpression of E2F-1 can induce apoptosis and may either promote or inhibit cellular proliferation, depending upon the cell type. In these studies overexpression of E2F-1 inhibited cyclin D1-dependent kinase activity, cyclin D1 protein levels, and promoter activity. The DNA binding domain, the pRB pocket binding region, and the amino-terminal Sp1 binding domain of E2F-1 were required for full repression of cyclin D1. Overexpression of pRB activated the cyclin D1 promoter, and a dominant interfering pRB mutant was defective in cyclin D1 promoter activation. Two regions of the cyclin D1 promoter were required for full E2F-1-dependent repression. The region proximal to the transcription initiation site at −127 bound Sp1, Sp3, and Sp4, and the distal region at −143 bound E2F-4–DP-1–p107. In contrast with E2F-1, E2F-4 induced cyclin D1 promoter activity. Differential regulation of the cyclin D1 promoter by E2F-1 and E2F-4 suggests that E2Fs may serve distinguishable functions during cell cycle progression. Inhibition of cyclin D1 abundance by E2F-1 may contribute to an autoregulatory feedback loop to reduce pRB phosphorylation and E2F-1 levels in the cell.

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Faculty Opinions recommendation of The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1006699.83556 ◽

2002 ◽

Author(s):

Andrius Kazlauskas

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Cyclin D1 ◽

Cell Cycle Progression ◽

Cycle Progression

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PARP14 regulates cyclin D1 expression to promote cell-cycle progression

Oncogene ◽

10.1038/s41388-021-01881-8 ◽

2021 ◽

Author(s):

Michael J. O’Connor ◽

Tanay Thakar ◽

Claudia M. Nicolae ◽

George-Lucian Moldovan

Keyword(s):

Cell Cycle ◽

Cyclin D1 ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Promote Cell Cycle Progression

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The retinoblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death

Oncogene ◽

10.1038/sj.onc.1202910 ◽

1999 ◽

Vol 18 (37) ◽

pp. 5239-5245 ◽

Cited By ~ 30

Author(s):

Karen E Knudsen ◽

Erich Weber ◽

Karen C Arden ◽

Webster K Cavenee ◽

James R Feramisco ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Tumor Suppressor ◽

Cell Cycle Progression ◽

Cellular Proliferation ◽

Cycle Progression ◽

Retinoblastoma Tumor Suppressor ◽

Retinoblastoma Tumor

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SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis

Blood ◽

10.1182/blood-2011-01-328765 ◽

2011 ◽

Vol 118 (3) ◽

pp. 723-735 ◽

Cited By ~ 28

Author(s):

Hedia Chagraoui ◽

Mira Kassouf ◽

Sreemoti Banerjee ◽

Nicolas Goardon ◽

Kevin Clark ◽

...

Keyword(s):

Cell Cycle ◽

Transcriptional Control ◽

Cell Cycle Progression ◽

Cellular Proliferation ◽

Loss Of Function ◽

Cycle Progression ◽

Cell Cycle Regulator ◽

Nuclear Changes ◽

Cytoplasmic Maturation

Abstract Megakaryopoiesis is a complex process that involves major cellular and nuclear changes and relies on controlled coordination of cellular proliferation and differentiation. These mechanisms are orchestrated in part by transcriptional regulators. The key hematopoietic transcription factor stem cell leukemia (SCL)/TAL1 is required in early hematopoietic progenitors for specification of the megakaryocytic lineage. These early functions have, so far, prevented full investigation of its role in megakaryocyte development in loss-of-function studies. Here, we report that SCL critically controls terminal megakaryocyte maturation. In vivo deletion of Scl specifically in the megakaryocytic lineage affects all key attributes of megakaryocyte progenitors (MkPs), namely, proliferation, ploidization, cytoplasmic maturation, and platelet release. Genome-wide expression analysis reveals increased expression of the cell-cycle regulator p21 in Scl-deleted MkPs. Importantly, p21 knockdown-mediated rescue of Scl-mutant MkPs shows full restoration of cell-cycle progression and partial rescue of the nuclear and cytoplasmic maturation defects. Therefore, SCL-mediated transcriptional control of p21 is essential for terminal maturation of MkPs. Our study provides a mechanistic link between a major hematopoietic transcriptional regulator, cell-cycle progression, and megakaryocytic differentiation.

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Akt/Protein Kinase B-Dependent Phosphorylation and Inactivation of WEE1Hu Promote Cell Cycle Progression at G2/M Transition

Molecular and Cellular Biology ◽

10.1128/mcb.25.13.5725-5737.2005 ◽

2005 ◽

Vol 25 (13) ◽

pp. 5725-5737 ◽

Cited By ~ 97

Author(s):

Kazuhiro Katayama ◽

Naoya Fujita ◽

Takashi Tsuruo

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Kinase Inhibitor ◽

Phosphorylation Site ◽

Cytoplasmic Localization ◽

M Cell ◽

Serine Threonine Kinase ◽

Cycle Progression ◽

M Phase ◽

Promote Cell Cycle Progression

ABSTRACT The serine/threonine kinase Akt is known to promote cell growth by regulating the cell cycle in G1 phase through activation of cyclin/Cdk kinases and inactivation of Cdk inhibitors. However, how the G2/M phase is regulated by Akt remains unclear. Here, we show that Akt counteracts the function of WEE1Hu. Inactivation of Akt by chemotherapeutic drugs or the phosphatidylinositide-3-OH kinase inhibitor LY294002 induced G2/M arrest together with the inhibitory phosphorylation of Cdc2. Because the increased Cdc2 phosphorylation was completely suppressed by wee1hu gene silencing, WEE1Hu was associated with G2/M arrest induced by Akt inactivation. Further analyses revealed that Akt directly bound to and phosphorylated WEE1Hu during the S to G2 phase. Serine-642 was identified as an Akt-dependent phosphorylation site. WEE1Hu kinase activity was not affected by serine-642 phosphorylation. We revealed that serine-642 phosphorylation promoted cytoplasmic localization of WEE1Hu. The nuclear-to-cytoplasmic translocation was mediated by phosphorylation-dependent WEE1Hu binding to 14-3-3θ but not 14-3-3β or -σ. These results indicate that Akt promotes G2/M cell cycle progression by inducing phosphorylation-dependent 14-3-3θ binding and cytoplasmic localization of WEE1Hu.

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