Co-expressed Cyclin D variants cooperate to regulate proliferation of germline nuclei in a syncytium

Abstract

The role of the G1-phase Cyclin D-CDK 4/6 regulatory module in linking germline stem cell (GSC) proliferation to nutrition is evolutionarily variable. In invertebrate Drosophila and C. elegans GSC models, G1 is nearly absent and Cyclin E is expressed throughout the cell cycle, whereas vertebrate spermatogonial stem cells have a distinct G1 and Cyclin D1 plays an important role in GSC renewal. In the invertebrate, chordate, Oikopleura, where germline nuclei proliferate asynchronously in a syncytium, we show a distinct G1-phase in which 2 Cyclin D variants are co-expressed. Cyclin Dd, present in both somatic endocycling cells and the germline, localized to germline nuclei during G1 before declining at G1/S. Cyclin Db, restricted to the germline, remained cytoplasmic, co-localizing in foci with the Cyclin-dependent Kinase Inhibitor, CKIa. These foci showed a preferential spatial distribution adjacent to syncytial germline nuclei at G1/S. During nutrient-restricted growth arrest, upregulated CKIa accumulated in arrested somatic endoreduplicative nuclei but did not do so in germline nuclei. In the latter context, Cyclin Dd levels gradually decreased. In contrast, the Cyclin Dbb splice variant, lacking the Rb-interaction domain and phosphodegron, was specifically upregulated and the number of cytoplasmic foci containing this variant increased. This upregulation was dependent on stress response MAPK p38 signaling. We conclude that under favorable conditions, Cyclin Dbb-CDK6 sequesters CKIa in the cytoplasm to cooperate with Cyclin Dd-CDK6 in promoting germline nuclear proliferation. Under nutrient-restriction, this sequestration function is enhanced to permit continued, though reduced, cycling of the germline during somatic growth arrest.

Inhibitory effect of simvastatin in nasopharyngeal carcinoma cells

“…In addition, FOXO transcription factors, which inhibit cyclin D1 expression and induce p27 expression, are also phosphorylated and inhibited by Akt pathway activation (34). Similarly, MAPK activation results in phosphorylation and stabilization of c-myc, which induces cyclin D1 and inhibits CKI expression (35,36). Taken together, the results of the present study indicate that statin-induced changes in endogenous cyclin and CDK could result from the inhibition of Akt and Erk1/2 in C666-1 cells.…”

Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/β-catenin signaling

“…With increased β-catenin translocated from cytoplasma to nucleus [ 11 , 12 ], the transcriptional activities of various downstream genes including cyclin D1, oct3/4, sox2, and nanog are strikingly stimulated [ 13 – 15 ]. The abundant expressions of sox2, oct3/4, and nanog represent the pluripotency of cancer stem cells (CSCs) [ 14 , 16 ], and cyclin D1 serves as a primary mediator in cell cycle maintenance [ 17 ]. Hence, the activation of Wnt/β-catenin may result in increased malignancy and continuous tumor cell proliferation.…”