Structure and dynamic regulation of Src-family kinases.

Src-family kinases are modular signaling proteins involved in a diverse array of cellular processes. All members of the Src family share the same domain organization, with modular SH3, SH2 and kinase domains followed by a C-terminal negative regulatory tail. X-ray crystallographic analyses of several Src family members have revealed critical roles for the SH3 and SH2 domains in the down-regulation of the kinase domain. This review focuses on biological, biophysical, and computational studies that reveal conformationally distinct active states within this unique kinase family.

The KEN box regulates Clb2 proteolysis in G1 and at the metaphase-to-anaphase transition.

Clb2 mitotic cyclin inhibits cell cycle progression by preventing mitotic exit and DNA synthesis. To allow cell cycle progression, Clb2 proteolysis is triggered by Cdc20 during the metaphase-to-anaphase (M-A) transition and by Hct1 during mitotic exit and G1 [1-6]. A cis element called the destruction box is required for this proteolysis [7-11]. Recently, an additional cis element called the "KEN box" was also shown to be required for proteolysis of human CDC20 and Securin [3,12]. Using a novel color assay, we show that a Clb2 KEN box is required to target a fusion protein containing the first 124 amino acids of Clb2 for proteolysis. We further show that full-length Clb2 bearing mutations in the KEN box is degraded efficiently during the M-A transition, but poorly during G1. If the destruction box of Clb2 is mutated in combination with mutation of the KEN box, then this form of Clb2 is more stable than Clb2 bearing either mutation by itself during both M-A and G1. Our results show that the KEN box and the destruction box act together during both M-A and G1 to regulate Clb2 proteolysis.

S-phase cyclins are required for a stable arrest at metaphase.

A critical DNA damage checkpoint in Saccharomyces cerevisiae is an arrest at the metaphase stage of mitosis. Here we show that the S-phase cyclins Clb5 and Clb6 are required for this arrest. Strains lacking Clb5 and Clb6 are hypersensitive to DNA damage. Furthermore, in the presence of the DNA alkylating agent methyl methanesulfonate (MMS) over 50% of clb5 clb6 mutants by-passed the metaphase checkpoint and arrested instead with separated sister chromatids. Levels of Pds1, an inhibitor of anaphase that accumulates following DNA damage, were similar in the wild-type and mutant strains following MMS treatment. Furthermore, unlike wild-type cells, clb5 clb6 mutants undergo nuclear division despite the presence of nuclear non-degradable Pds1. Our results suggest a novel role for the S-phase cyclins Clb5 and Clb6 in maintaining sister chromatid cohesion during a metaphase arrest, perhaps by regulating Pds1 activity.

Irreducible volar dislocation of the proximointerphalangeal joint.

Volar dislocations of the proximointerphalangeal joint are not injuries to be treated lightly. If the dislocation reduces easily, a tear of the central tendon would be indicated and immediate open repair of this structure then becomes mandatory. If the dislocation is irreducible, then a tear of the collateral ligament with button-holing of the head of the proximal phalanx through the interval between the central tendon and the lateral band should be suspected, and open reduction and replacement of these structures in their normal position is indicated. The results after open repair of irreducible dislocations may be more favorable than dislocations that reduce easily. The extensor mechanism is intact and as the joint need not be held for long periods of time, motion can be started early and stiffness avoided.

Fractures of the hip in the institutionalized psychotic patient. A mortality and morbidity survey of 106 cases.

Fractures of the hip and its resultant mortality are a reflection of age more than any other factor. The death and morbidity in this poor risk patient group with multiple medical problems can be significantly lowered by the generalized use of prophylactic antibiotics and thromboembolic protection. Stabilization of intertrochanteric fractures at the time of surgery with stronger implants, displacement osteotomy, and the judicious use of bone cement, along with primary replacement of displaced subcapital fractures allows the patient earlier ambulation before the skills of walking have been forgotten.

Closed rupture of the anterior tibial tendon. A case report and review of the literature.

Closed rupture of the anterior tibial tendon is an unusual injury. It occurs in middle-aged to elderly males following forced plantar flexion of the ankle. A case is presented of a 69-year-old man with spondylolisthesis whose tendon ruptured during a physical examination. The injury was thought initially to represent an acute L5 root compression secondary to a herniated intervertebral disc at the level of his spondylolisthesis. The correct diagnosis was made after admission to the hospital. Surgical repair of the tendon resulted in normal ankle motion and strength. A review of the 12 previously reported cases indicates that treatment has been either surgical repair or conservative management. All patients recovered a normal gait but those treated surgically had more motion and dorsiflexion strength. This condition emphasizes the importance of exact history taking and thorough physical examination.