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.

细胞周期蛋白 D1编码全酶的调节亚基，该全酶磷酸化 RB 并作为协同核癌基因发挥作用。丝氨酸苏氨酸激酶 Akt 在细胞代谢、存活和促有丝分裂信号传导的控制中起着关键作用。在此，Akt1 介导的乳腺下游底物磷酸化被细胞周期蛋白 D1基因缺失减少，并由乳腺靶向细胞周期蛋白 D1诱导过度表达。细胞周期蛋白 D1 与 Akt1 相关，并增加有丝分裂原诱导的起始速率和最大细胞 Akt1 活性。细胞周期蛋白 D1 在细胞质膜相关池中被识别，细胞质膜定位的细胞周期蛋白 D1——而非核定位的细胞周期蛋白 D1——概括了 Akt1 的转录功能。这些研究确定了细胞周期蛋白 D1 的一种新的核外功能，可通过增强 Ser473 位点的 Akt1 磷酸化来增强增殖功能。