Abstract B10: Cyclin D1 restrains oncogene-induced autophagy via phosphorylation of LKB1

Abstract

Abstract Cyclin D1 is an important molecular driver of many human cancers. The cyclin D1 gene is amplified or overexpressed in up to half of human breast cancers and mammary-targeted overexpression of cyclin D1 is sufficient to induce mammary tumorigenesis in mice. Cyclin D1 encodes the regulatory subunit of the cyclin-dependent kinase (CDK) holoenzyme that phosphorylates several substrates including the retinoblastoma protein (pRb) to advance the G1S cell cycle checkpoint and promote DNA synthesis. Recent studies have implicated cell cycle regulators that govern G1S transition, in regulating cellular metabolism. Cyclin D1 phosphorylates and inactivates a nuclear encoded protein essential for mitochondrial biogenesis, Nrf1. In this manner cyclin D1 coordinates both nuclear and mitochondrial functions. Consistent with cyclin D1-dependent inhibition of mitochondrial biogenesis, pRB promotes and E2F-1 inhibits mitochondrial biogenesis. In addition to inhibiting mitochondrial biogenesis, cyclin D1 inhibits mitochondrial membrane potential, which may be in part due to binding VDAC. Autophagy is a catabolic pathway activated in response to cellular stress such as oxidative or nutritional stress. It mitigates cellular damage via removal of insoluble and damaged proteins, lipids and organelles. Autophagy is enhanced by the phosphorylated and activated form of 5’-AMP-activated protein kinase (AMPK). We initiated the following study to directly test the effect of cyclin D1 has on cellular metabolism and autophagy. Herein, endogenous cyclin D1 restrained autophagy in breast cancer cells in tissue culture and in the mammary gland of mice. Using mammary epithelial-targeted deletion of cyclin D1 we show cyclin D1 restrains autophagy by reducing AMPK activation. Cyclin D1 may serve to couple cellular proliferation to cellular energy homeostasis. Citation Format: Mathew Casimiro, Gabriele Di Sante, Emanuele Loro, Timothy Pestell, Sara Bisetto, Marco Velasco-Velázquez, Xuanmao Jiao, Zhiping Li, Chenguang Wang, Daniel Ly, Bin Zheng, Shen Che-Hung, Adam Ertel, Richard G. Pestell. Cyclin D1 restrains oncogene-induced autophagy via phosphorylation of LKB1. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B10.