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Activity of hepatocyte nuclear factor 1alpha and hepatocyte nuclear factor 1beta isoforms is differently affected by the inhibition of protein phosphatases 1/2A.

ABSTRACT: Phosphorylation/dephosphorylation processes are known to control the activity of several transcription factors. The nutrition-dependent expression of sucrase-isomaltase and Na+/glucose co-transporter 1, two proteins implicated in the intestinal absorption of glucose, has been shown to be closely related to modifications of hepatocyte nuclear factor 1 (HNF1) activity. This study was conducted to determine whether phosphorylation/dephosphorylation processes could control HNF1 activity. We show that expression of the gene encoding sucrase-isomaltase is inhibited in the enterocytic Caco-2 clone TC7 by okadaic acid at a concentration that is known to inhibit protein phosphatases 1/2A and that does not affect cell viability. At the same concentration, phosphorylation of the HNF1alpha and HNF1beta isoforms is greatly enhanced and their DNA-binding capacity is decreased. The phosphorylation state of HNF1beta isoforms directly affects their DNA-binding capacity. In contrast, the decreased DNA-binding activity of the HNF1alpha isoforms, which was observed after the inhibition of protein phosphatases 1/2A, is due to a net decrease in their total cellular and nuclear amounts. Such an effect results from a decrease in both the HNF1alpha mRNA levels and the half-life of the protein. This is the first evidence for the implication of protein phosphatases 1/2A in the control of the activity of HNF1 isoforms. Moreover, these results emphasize a physiological role for the balance between phosphatases and kinases in the nutrition-dependent regulation of HNF1-controlled genes.

SUBMITTER: Carriere V

PROVIDER: S-EPMC1221656 | biostudies-other | 2001 Mar

REPOSITORIES: biostudies-other

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