北海道大学 大学院理学研究院 化学部門

生物化学研究室

講演者

松浦 功 博士
(Division of Molecular Genetidcs and Medicine, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan, R.O.C.)

日時

平成18年11月14日（金）　16:30 – 18:00

場所

北海道大学理学部　7号館2階　2-12（会議室）

概要

Pleiotropic cytokine transforming growth factor- (TGF- ) is a prototypic member of a large family of cytokines that control numbers of fundamental cellular behavior such as cell proliferation, differentiation and apoptosis.
TGF- signal transduction is mediated by two types of cell surface receptors: typeI and type II Ser/Thr receptor kinases; and downstream effectors, Smad family proteins. Binding ligand induces complex formation between the two types of receptors that can directly phosphorylate Smad2/3 (Receptor-regulated Smads or R-Smads) at their specific C-terminal Ser residues. The C-terminally phosphorylated Smad2/3 then complex with Smad4 (Common-mediator Smad or Co-Smad), translocate to nucleus, where they collaborate with other cofactors to regulate the target genes.
TGF- is a natural and potent growth inhibitor of many normal cell types. The loss of cytostatic response to TGF- is closely correlated with hyperproliferative disorders and progression of many types of cancer. Cancer cells often become refractory to the growth inhibitory effects of TGF- with all the signal transduction components intact, indicating the epigenetic or functional inactivation of the components in this growth inhibitory pathway.
Although TGF- is a potent cell growth inhibitor in most of normal cells, elevated level of TGF- is also associated with advanced malignant tumors. This observation suggested the possibility that the property of TGF- /Smad signaling switches from tumor suppressor to promoter during cancer progression.
As central mediators in TGF- signal transduction, activity of Smads is under tight regulation. Association of regulatory proteins or posttranscriptional modifications such as ubiqitination or phosphorylation can influence the Smad activity.
Targeted gene disruption studies have shown that Smad3 is a growth inhibitor and necessary for TGF- dependent cytostatic response. This effect is accompanied by downregulation of growth promoter c-Myc and upregulation of cyclin-dependent kinase (CDK) inhibitors p15 and p21. These events lead to inactivation of G1 CDKs and eventually to cell cycle arrest. Using a series of custom phospho-specific antibodies, we have recently demonstrated multiple sites in Smad3, Thr8, T178 and Ser212, could be phosphorylated by G1 CDKs, CDK4 and CDK2. Mutation of these sites to nonphosphorylatable residues augmented Smad3 activity: downregulating c-Myc, upregulating p15, and inhibiting cell growth. Thus CDK-catalyzed phosphorylation negatively regulates antiproliferative function of Smad3. This finding established a novel negative feedback mechanism in the Smad3-mediated cytostatic pathway. Erk MAP kinases can also phosphorylate Smad3 at partially overlapped sites (Thr178, Ser203 and Ser207) to inhibit its activity. Because cancer cells often contain elevated levels of G1 CDK activity as well as Erk activity, increased Smad3 phosphorylation in those sites may contribute to the resistance to TGF- -mediated growth inhibition and to tumorigenesis.

連絡先

北海道大学 大学院先端生命科学研究院 先端生命科学部門
矢澤 道生
TEL: 011-706-3813