Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Bluemle Life Sciences Building, 233 South 10(th) Street, Philadelphia, PA 19107, USA.
Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA 19096, USA.
Cell Rep. 2020 Sep 15;32(11):108151. doi: 10.1016/j.celrep.2020.108151.
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.
周期蛋白 D1 编码全酶的调节亚基，该全酶可使 RB 磷酸化，并作为协同核癌基因发挥作用。丝氨酸苏氨酸激酶 Akt 在控制细胞代谢、存活和有丝分裂信号转导中起着关键作用。在此，通过基因敲除周期蛋白 D1 降低了乳腺中 Akt1 介导的下游底物的磷酸化，而乳腺靶向过表达周期蛋白 D1 则诱导其磷酸化。周期蛋白 D1 与 Akt1 相关，并增强了有丝分裂原诱导的 Akt1 活性的起始速度和最大细胞活性。在细胞质膜相关池中鉴定到周期蛋白 D1，并且细胞质膜定位的周期蛋白 D1-而不是核定位的周期蛋白 D1-再现了 Akt1 的转录功能。这些研究确定了周期蛋白 D1 的一种新的核外功能，通过增强 Akt1 在 Ser473 处的磷酸化来增强增殖功能。
