Basic Pan-Cancer Analysis of the Carcinogenic Effects of Cyclin-Dependent Kinase 4 (CDK4) in Human Surface Tumors

Although the evidence based on current human, animal, or molecular biology can explain some of the relationships between CDK4 and cancer, there is no pan-cancer analysis of the gene CDK4 in human skin tumors. Therefore, the potential carcinogenic effects of CDK4 in 33 tumors were initially explored in the datasets of the GEO (Gene Expression Omnibus) and the CGA (Cancer Genome Atlas). We found that CDK4 was highly expressed in most cancers and that CDK4 performance levels significantly correlated with the prognosis of cancer patients. These were found in our preliminary exploration. In addition, we used the dataset in tumors such as cutaneous melanoma or lung adenocarcinoma and found increased levels of phosphorylation of r24 l/C/h/s. In addition, fibroblast infiltration associated with CDK4 cancer was observed in head and neck, sarcoma, and melanoma skin. Using this pan-cancer study, our group has provided a comprehensive preliminary demonstration of the oncogenic effects of the CDK4 gene on different human skin tumors.

Induced ATF-2 represses CDK4 transcription through dimerization with JunD inhibiting intestinal epithelial cell growth after polyamine depletion

Intestinal epithelium is a rapidly self-renewing tissue in the body, and its homeostasis is tightly regulated by numerous factors including polyamines. Decreased levels of cellular polyamines increase activating transcription factor (ATF)-2, but the exact role and mechanism of induced ATF-2 in the regulation of intestinal epithelial cell (IEC) growth remain elusive. Cyclin-dependent kinase (CDK) 4 is necessary for the G1-to-S phase transition during the cell cycle, and its expression is predominantly controlled at the transcription level. Here, we reported that induced ATF-2 following polyamine depletion repressed CDK4 gene transcription in IECs by increasing formation of the ATF-2/JunD heterodimers. ATF-2 formed complexes with JunD as measured by immunoprecipitation using the ATF-2 and JunD antibodies and by glutathione S-transferase (GST) pull-down assays using GST-ATF-2 fusion proteins. Studies using various mutants of GST-ATF-2 revealed that formation of the ATF-2/JunD dimers depended on the COOH-terminal basic region-leucine zipper domain of ATF-2. Polyamine depletion increased ATF-2/JunD complex and inhibited CDK4 transcription as indicated by a decrease in the levels of CDK4-promoter activity and its mRNA. ATF-2 silencing not only prevented inhibition of CDK4 transcription in polyamine-deficient cells but also abolished repression of CDK4 expression induced by ectopic JunD overexpression. ATF-2 silencing also promoted IEC growth in polyamine-depleted cells. These results indicate that induced ATF-2/JunD association following polyamine depletion represses CDK4 transcription, thus contributing to the inhibition of IEC growth.