No abstract

DNA replication stress triggers the activation of Checkpoint Kinase 1 (Chk1) in a pathway that requires the independent chromatin loading of the ATRIP-ATR (ATR-interacting protein/ATM [ataxia-telangiectasia mutated]-Rad3-related kinase) complex and the Rad9-Hus1-Rad1 (9-1-1) clamp. We show that Rad9's role in Chk1 activation is to bind TopBP1, which stimulates ATR-mediated Chk1 phosphorylation via TopBP1's activation domain (AD), a domain that binds and activates ATR. Notably, fusion of the AD to proliferating cell nuclear antigen (PCNA) or histone H2B bypasses the requirement for the 9-1-1 clamp, indicating that the 9-1-1 clamp's primary role in activating Chk1 is to localize the AD to a stalled replication fork.Supplemental material is available at http://www.genesdev.org.

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Objective. To determine whether interleukin-1 (IL-1) or tumor necrosis factor ␣ (TNF␣), or both, plays a role in the excessive degradation that is observed in cultured osteoarthritic (OA) articular cartilage.Methods Conclusion. These results suggest that the autocrine/paracrine activities of TNF␣ and IL-1 in articular cartilage may play important roles in cartilage matrix degradation in OA patients but not in all patients. Inhibition of either or both of these cytokines may offer a useful therapeutic approach to the management of OA by reducing gene expression of MMPs involved in cartilage matrix degradation and favoring its repair.Osteoarthritis (OA) is a slowly progressive degenerative disease characterized by early loss of the tensile strength of articular cartilage (1), which is produced by a fibrillar network composed of type II collagen (CII) (1,2). Excessive degradation of CII (3,4), such as that induced by collagenase, is a feature of OA (5-7) and rheumatoid arthritic (3) articular cartilage. The compressive stiffness of joint cartilage depends on the swelling pressure achieved by hydration of proteoglycan (1). Thus, the net loss of proteoglycan that occurs in the early stage of OA results in reduced stiffness of the cartilage (1,6).