Abstract B33: The membrane associated cyclin D1 promotes contact-independent growth via phosphorylation of Akt1 Ser 473

Abstract

Abstract The serine threonine kinase Akt plays a pivotal role in the control of cellular metabolism, survival, growth and cellular migration. Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates pRb, to promote cell cycle progression and functions as a nuclear collaborative oncogene. Herein, genetic deletion of cyclin D1 reduced and overexpression induced Akt1 activity in tissue culture and in vivo. Endogenous cyclin D1 augmented both the rate of onset and maximal cellular Akt1 activity. The cytoplasmic membrane-associated pool of cyclin D1, augmented Akt1 kinase activity, to thereby induce cell cycle progression, cellular migration, proliferation and contact independent growth. The induction of Akt1 kinase activity, via Ser 473, was dependent upon a single residue of cyclin D1 (K112) in vitro, and in vivo in mammary epithelial cell targets tissue specific transgenic mice. Distinct subcellular compartments of cell cycle proteins convey distinct functions to augment cellular growth. Our data identified the function of the membrane associated cyclin D1 pool is to phosphorylate and activate AKT1, thereby, inducing cell cycle progression, contact independent growth and cellular migration. Membrane mounted cyclin D1 is a novel targetable vulnerability aberrant growth control. Citation Format: Xuanmao Jiao, Ke Chen, Shaohua Xu, Xiaoming Ju, Adam Ertel, Lifeng Tian, Zuoren Yu, Gabriele Di Sante, Min Wang, Zhiping Li, Timothy Pestell, Mathew Casimiro, Duanwen Shen, Samuel Achilefu, Richard Pestell. The membrane associated cyclin D1 promotes contact-independent growth via phosphorylation of Akt1 Ser 473. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B33.