RNA polymerase I stability couples cellular growth to metal availability.

Zinc is an essential cofactor of all major eukaryotic RNA polymerases. How the activity of these enzymes is coordinated or regulated according to cellular zinc levels is largely unknown. Here we show that the stability of RNA polymerase I (RNAPI) is tightly coupled to zinc availability in vivo. In zinc deficiency, RNAPI is specifically degraded by proteolysis in the vacuole in a pathway dependent on the export in Xpo1p and deubiquitination of the RNAPI large subunit Rpa190p by Ubp2p and Ubp4p. RNAPII is unaffected, which allows for the expression of genes required in zinc deficiency. RNAPI export to the vacuole is required for survival during zinc starvation, suggesting that degradation of zinc-binding subunits might provide a last resort zinc reservoir. These results reveal a hierarchy of cellular transcriptional activities during zinc starvation and show that degradation of the most active cellular transcriptional machinery couples cellular growth and proliferation to zinc availability.

PHLPPing through history: a decade in the life of PHLPP phosphatases.

In the decade since their discovery, the PH domain leucine-rich repeat protein phosphatases (PHLPP) have emerged as critical regulators of cellular homeostasis, and their dysregulation is associated with various pathophysiologies, ranging from cancer to degenerative diseases, such as diabetes and heart disease. The two PHLPP isozymes, PHLPP1 and PHLPP2, were identified in a search for phosphatases that dephosphorylate Akt, and thus suppress growth factor signaling. However, given that there are over 200 000 phosphorylated residues in a single cell, and fewer than 50 Ser/Thr protein phosphatases, it is not surprising that PHLPP has many other cellular functions yet to be discovered, including a recently identified role in regulating the epigenome. Both PHLPP1 and PHLPP2 are commonly deleted in human cancers, supporting a tumor suppressive role. Conversely, the levels of one isozyme, PHLPP1, are elevated in diabetes. Thus, mechanisms to correctly control PHLPP activity in cells are critical for normal cellular homeostasis. This review summarizes the known functions of PHLPP and its role in disease.

Adiponectin, resistin and leptin response to dietary intervention in diabetic nephropathy.

OBJECTIVE: Adipokines play an important role in metabolic regulations. Obesity, diabetes, and renal disturbances affect adipokine profile by influencing their complex effects on metabolism. Our objective was to assess the effect of low-energy diet intervention on serum adiponectin, leptin, and resistin levels in diabetic nephropathy. METHODS: Seventeen subjects with diabetes type 2 and nephropathy participated in the study. After estimation of individual resting metabolic rates by indirect calorimetry, diets introducing 20% energy deficit were applied. At baseline and after 2 months of dieting, the following parameters were measured: body composition by dual x-ray spectrometry and serum adiponectin (Adp), leptin (Lep), resistin (Res), insulin, urea, creatinine, glucose, glycosylated hemoglobin, C-reactive protein, and tumor necrosis factor-alpha concentrations. Homeostatic model assessment (HOMA) was used to quantify insulin resistance. RESULTS: Total energy, protein, and fat intakes diminished significantly with intentional dieting. Significant decreases in total body fat mass (FM) and its percentage in body mass (FM%) and trunk and gynoid fat mass, as well as in serum resistin and tumor necrosis factor-alpha levels, were also observed. Responses of adipokines to dietary treatment varied individually. Generally, they were affected by FM. Alterations in Lep concentrations correlated negatively with baseline FM, FM%, and android and gynoid fat mass and positively with changes in intake of protein, carbohydrates, and total energy of the consumed diet. Changes in Adp were inversely related to FM after therapy. Alterations in Res concentrations correlated positively with android fat mass before therapy and initial Lep levels. Adiponectin was inversely related to HOMA index before and after treatment. CONCLUSIONS: Low-energy diet applied in diabetic nephropathy may decrease serum resistin levels and inflammation. In addition, responses of all adipokines to dieting appear to be affected by body fat mass, especially android fat mass.