Publications (2)9.55 Total impact
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Article: Smad-mediated transcription is required for transforming growth factor-beta 1-induced p57(Kip2) proteolysis in osteoblastic cells.
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ABSTRACT: Cyclin-dependent kinase inhibitory proteins (CKIs) are negative regulators of the cell cycle. Of all CKIs, only p57(Kip2) plays an essential role(s) that other CKIs cannot compensate for in embryonic development. Recently, we found that p57(Kip2) is degraded through the ubiquitin-proteasome pathway in osteoblastic cells stimulated to proliferation by transforming growth factor (TGF)-beta1 (Urano, T., Yashiroda, H., Muraoka, M., Tanaka, K., Hosoi, T., Inoue, S., Ouchi, Y., and Toyoshima, H. (1999) J. Biol. Chem. 274, 12197-12200). We report here that TGF-beta1-induced p57(Kip2) proteolysis is mediated through transcription by the Smad pathway. When the constitutively active form of the TGF-beta type I receptor ALK-5(TD) was ectopically expressed in osteoblastic cells, p57(Kip2) that had been accumulated by serum starvation causing the cell-cycle arrest was rapidly degraded in a manner analogous to TGF-beta1 stimulation. Moreover, Smad2 or Smad3 with Smad4 enhanced the proteolytic pathway of p57(Kip2). The degradation of p57(Kip2) evoked by TGF-beta1 was blocked by forced expression of an inhibitory Smad called Smad7 or by the addition of actinomycin D or alpha-amanitin. These results indicate that accelerated degradation of p57(Kip2) by TGF-beta1/Smad signaling is mediated through a newly synthesized factor(s) that modifies p57(Kip2) or the ubiquitin-proteasome pathway.Journal of Biological Chemistry 05/2001; 276(14):10700-5. · 4.77 Impact Factor -
Article: Hyperosmolarity-induced gene stimulation is mediated by the negative calcium responsive element.
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ABSTRACT: The negative calcium responsive elements of the parathyroid hormone gene bind to a specific set of nuclear proteins in an extracellular calcium (Ca2+e)-dependent manner. We have found that one of the negative calcium responsive elements, named oligo B, is found in the 5'-flanking region of such vasoactive genes as the vasopressin and atrial natriuretic polypeptide genes. Furthermore, the oligo B-like sequence in the former gene is conserved throughout evolution. Because expression of some of these vasoactive genes is altered by external stimuli which change cell volume, we examined whether oligo B is involved in gene regulation by hyperosmolarity. Here, we demonstrate that the binding between oligo B and its binding nuclear proteins including a redox factor 1 was reduced by hyperosmolarity generated by sodium chloride but not by urea. Such attenuated binding was reversed by dephosphorylating nuclear proteins by a potato acid phosphatase, suggesting that NaCl treatment elicited phosphorylation of these nuclear proteins to weaken their binding activity to oligo B. Furthermore, these nuclear events led to hyperosmolarity-mediated transcriptional stimulation of the genes bearing this DNA element in the cultured cells.Journal of Biological Chemistry 01/1998; 272(51):32274-9. · 4.77 Impact Factor
