Hanley, S. E. | Search bioRxiv

bioRxiv2024

Cyclin C Promotes Pancreatic Development and Suppresses Cancer Initiation Through Maintenance of the Autophagy-Lysosome Pathway

The cyclin C (Ccnc)-Cdk8/Cdk19 kinases are components of the Mediator that represses or activates gene transcription. The present study found that Ccnc is required for both steady state and induced autophagic gene transcription in mouse embryonic fibroblasts. In vivo, pancreatic ablation of Ccnc (CcncPan{Delta}) resulted in phenotypes (islet atrophy, acinar cell damage) also observed in autophagy deficient models. However, CcncPan{Delta}animals displayed more dramatic phenotypes including earlier death and accelerated acinar ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) precancerous lesion formation when these animals also expressed oncogenic KrasG12D. Consistent with the in vivo results, a KrasG12D; CcncPan{Delta} pancreatic derived cell line displayed reduced autophagy lysosome pathway (ALP) activation. Although autophagy deficient acinar cells undergo Tp53-dependent cell death, histopathology revealed that KrasG12D;Ccnc-/- (PC) pancreata did not allowing damaged cells to keep dividing. Therefore, Ccnc both supports normal ALP function protecting endocrine and exocrine cell but also kills damaged cells before they become malignant. Finally, the PC cell line displayed reduced proteasome function rendering cells hypersensitive to proteasome inhibitors. This hypersensitivity was also observed in disparate Ccnc-/- tumor cell lines or in Ccnc+/+ tumor cells co-treated with Cdk8/Cdk19 inhibitors. These findings suggest a new avenue to target pancreatic neoplasms by inhibiting cyclin C-Cdk8/Cdk19 proteasome activity.

developmental biology↗

bioRxiv2020

Snx4-mediated nucleophagy targets transcription factors controlling ATG gene expression

Autophagy is controlled in part by the repression and activation of Autophagy-related (ATG) gene transcription. Here, we demonstrate that the conserved Cdk8 Kinase Module (CKM) of the mediator complex represses transcription of several ATG genes. To relieve this repression following nitrogen starvation, Med13 is rapidly degraded via a novel selective autophagy mechanism. This pathway requires the core autophagy machinery but is independent of known nucleophagy systems. It requires the cytosolic filament nucleoporin Gle1, the sorting nexin Snx4-Atg20 heterodimer, and the scaffold protein Atg17. This suggests a model where Med13 traverses through the nuclear pore complex, passing from Gle1 to Snx4. Snx4 then transports Med13 to autophagosomes by binding to Atg17. This previously unidentified nucleophagy pathway also mediates the autophagic degradation of two transcriptional activators of ATG genes (Rim15, Msn2) suggesting that this mechanism targets transcription factors that regulate ATG expression. This system provides a new level of selectivity, permitting the cell to fine-tune the autophagic response by controlling the turnover of both positive and negative ATG transcription factors.

cell biology↗