1020

CDK5

epithelial-mesenchymal transition is a change of cellular plasticity critical for embryonic development and tumor metastasis. CDK5 is a proline-directed serine/threonine kinase playing important roles in cancer progression. Here we show that CDK5 is commonly overexpressed and significantly correlated with several poor prognostic parameters of breast cancer. We found that CDK5 participated in TGF-beta1-induced EMT. In MCF10A, TGF-beta1 upregulated the CDK5 and p35 expression, and CDK5 knockdown inhibited TGF-beta1-induced EMT. CDK5 overexpression also exhibited a potential synergy in promoting TGF-beta1-induced EMT. In mesenchymal breast cancer cells MDA-MB-231 and BT549, CDK5 knockdown suppressed cell motility and tumorigenesis. We further demonstrated that CDK5 modulated cancer cell migration and tumor formation by regulating the phosphorylation of FAK at Ser-732. Therefore, CDK5-FAK pathway, as a downstream step of TGF-beta1 signaling, is essential for EMT and motility in breast cancer cells. This study implicates the potential value of CDK5 as a molecular marker for breast cancer.

Cyclin-dependent kinase 5 (CDK5) has been documented in podocyte injuries in diabetic nephropathy (DN), however its role in renal tubular epithelial cells has not been elucidated. We report here that CDK5 is detrimental and promotes tubulointerstitial fibrosis (TIF) via the extracellular signal-regulated kinase 1/2 (ERK1/2)/peroxisome proliferator-activated receptor gamma (PPRAgamma) pathway in DN. In high glucose cultured NRK52E cells, blocking CDK5 activity inhibited epithelial-to-mesenchymal transition (EMT) and fibrosis via ERK1/2/PPARgamma pathway. In diabetic rats, CDK5 inhibitor roscovitine decreased renal fibrosis and improved renal function as demonstrated by a decrease in levels of blood urine nitrogen (BUN), serum creatinine and beta2-microglobulin. Further studies revealed that improved renal fibrosis and function in diabetic rats were associated with inactivation of ERK1/2 and PPARgamma signaling pathways. In late staged DN patients, the upregulation of CDK5 and p35 activated phosphorylated ERK1/2 and PPARgamma, leading to decreased levels of E-cadherin but increased Vimentin and Collagen IV. Accordingly, renal fibrosis and function were worsened as revealed by decreased estimated glomerular filtration rate (eGFR) and increased serum BUN, creatinine, beta2-microglobulin, 24-hour proteinuria and urine albumin to creatinine ratio (UACR). These findings demonstrate a novel mechanism that CDK5 increases tubulointerstitial fibrosis by activating the ERK1/2/PPARgamma pathway and EMT in DN. CDK5 might have therapeutic potential in diabetic nephropathy.