Endogenous Cyclin D1 Promotes the Rate of Onset and Magnitude of Mitogenic Signaling via Akt1 Ser473 Phosphorylation

Ke Chen; Xuanmao Jiao; Agnese Di Rocco; Duanwen Shen; Shaohua Xu; Adam Ertel; Zuoren Yu; Gabriele Di Sante; Min Wang; Zhiping Li; Timothy G Pestell; Mathew C Casimiro; Emmanuel Skordalakes; Samuel Achilefu; Richard G Pestell

doi:10.1016/j.celrep.2020.108151

Endogenous Cyclin D1 Promotes the Rate of Onset and Magnitude of Mitogenic Signaling via Akt1 Ser473 Phosphorylation

Cell Rep. 2020 Sep 15;32(11):108151. doi: 10.1016/j.celrep.2020.108151.

Authors

Affiliations

¹ Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Bluemle Life Sciences Building, 233 South 10(th) Street, Philadelphia, PA 19107, USA.
² Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA 19096, USA.
³ Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, USA.
⁴ Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA 19096, USA; Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
⁵ Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA 19096, USA; Abraham Baldwin Agricultural College, Department of Science and Mathematics, Box 15, 2802 Moore Highway, Tifton, GA 31794, USA.
⁶ The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
⁷ Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, USA; Department of Radiology, Washington University, St. Louis, MO 63110, USA; Departments of Biochemistry & Molecular Biophysics, Washington University, St. Louis, MO 63110, USA.
⁸ Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA 19096, USA; The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA. Electronic address: richard.pestell@bblumberg.org.

Abstract

Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates RB and functions as a collaborative nuclear oncogene. The serine threonine kinase Akt plays a pivotal role in the control of cellular metabolism, survival, and mitogenic signaling. Herein, Akt1-mediated phosphorylation of downstream substrates in the mammary gland is reduced by cyclin D1 genetic deletion and is induced by mammary-gland-targeted cyclin D1 overexpression. Cyclin D1 is associated with Akt1 and augments the rate of onset and maximal cellular Akt1 activity induced by mitogens. Cyclin D1 is identified in a cytoplasmic-membrane-associated pool, and cytoplasmic-membrane-localized cyclin D1-but not nuclear-localized cyclin D1-recapitulates Akt1 transcriptional function. These studies identify a novel extranuclear function of cyclin D1 to enhance proliferative functions via augmenting Akt1 phosphorylation at Ser473.

Keywords: Akt1; breast cancer; cyclin D1; phosphorylation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

3T3 Cells
Animals
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Cell Membrane / metabolism
Cyclin D1 / genetics
Cyclin D1 / metabolism*
Cyclin-Dependent Kinases / metabolism
Female
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
MCF-7 Cells
Mammary Glands, Animal / metabolism
Mice
Mice, Transgenic
Mitogens / metabolism*
Phosphorylation
Phosphoserine / metabolism*
Protein Binding
Proto-Oncogene Proteins c-akt / chemistry
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism*
Signal Transduction*
Transcription, Genetic

Substances

Mitogens
Cyclin D1
Phosphoserine
Proto-Oncogene Proteins c-akt
Cyclin-Dependent Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding