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עמוד בית
Mon, 17.06.24

April 2006

Ubiquitin Wins Nobel
G. Asher and Y. Shaul

Ubiquitin-proteasome degradation is a key cellular process involved in almost every aspect of cell life. According to the current concept, proteins are stable unless they are marked by poly-ubiquitination for degradation by the 26S proteasomes. A new twist in the concept became evident while studying the degradation of the tumor suppressor p53, a protein that appeared to satisfy this principle. We have discovered that native p53 is also prone to ubiquitin-independent 20S proteasomal degradation, suggesting that certain proteins are inherently unstable. We further found that this process of degradation is mediated by 20S proteasomes and inhibited by NADH quinone oxidoreductase 1. Our recent findings together with previous observations of ubiquitin-independent degradation suggest the existence of ubiquitin-independent mechanisms for proteasomal protein degradation in the cells.


Y. Mosesson and Y. Yarden

Polyubiquitylation of cellular proteins has long been recognized as a prelude to a degradative fate in proteasomes. In recent years, however, ubiquitin conjugation has emerged as a regulatory strategy of considerable versatility. Most notably, monoubiquitylation is attributed an intimate role in trafficking of membrane proteins between various cellular compartments. Diverse classes of transmembrane proteins from across the eukaryotic spectrum (e.g., epidermal growth factor-receptor and other receptor tyrosine kinases) become modified with monoubiquitin molecules. Monoubiquitylation of substrates, in turn, regulates both their endocytosis at the plasma membrane and sorting in endosomes for delivery to lysosomes or vacuoles. A mechanistic rationale lies in the identification of a growing list of ubiquitin-binding domains carried by a variety of endocytic adaptor proteins. Thus, ubiquitin-conjugated membrane proteins may form extensive contacts with the endocytic machinery. Further, ubiquitin-binding adaptors and other endocytic components are, likewise, often monoubiquitylated. In this case, ubiquitin conjugation may serve to enhance intermolecular avidity in cargo-bound endocytic complexes, or alternatively, to mediate timely inactivation of ubiquitin-binding adaptors. Interestingly, the ubiquitin/endocytosis interface is appropriated by pathogenic organisms, for instance, during budding of viruses from host-infected cells. Moreover, compromised ubiquitin-mediated transport of certain signaling receptors is associated with disease states, including oncogenic transformation.



E. Rabinovich, D. Bussi, I. Shapira, G. Alalouf, C. Lipson, Y. Elkabetz, M. Glickman, M. Bajorek and S. Bar-Nun
D. Kornitzer
Distinct fungal species exhibit different cellular morphologies, such as yeast and filamentous (hyphal and pseudohyphal) forms, that are reflected in the macroscopic colony morphology. Dimorphic and multimorphic fungi can switch between these different morphologies, enabling the utilization of different food supplies in the case of saprophytes, and contributing to pathogenesis in the case of parasites. Cellular morphogenesis is often regulated by signal transduction pathways, and is intimately linked to the cell cycle machinery. Here we describe the role of ubiquitin-mediated degradation of cell cycle regulators and transcription factors involved in fungal morphogenesis
L. Kaplun, Y. Ivantsiv, A. Bakhrat, R. Tzirkin, K. Baranes, N. Shabek, and D. Raveh

We describe a unique E3, the F-box protein, Ufo1, of yeast. Ufo1 recruits the mating switch endonuclease, Ho, to the SCF complex for ubiquitylation. In addition to the F-box and WD40 protein-protein interaction domains found in all F-box proteins, Ufo1 has a unique domain comprising multiple copies of the ubiquitin-interacting motif. Ufo1 interacts with the UbL-UbA protein, Ddi1, via its UIMs[1], and this is required for turnover of SCF Ufo1 complexes. This is a novel function for an UbL-UbA protein. Deletion of the genomic UFO1 UIMs is lethal and our data indicate that Ufo1ΔUIM acts as a dominant negative leading to inhibition of the SCF pathway of substrate degradation and to cell cycle arrest. Furthermore, we found that Ddi1 is required for the final stages of degradation of Ho endonuclease. In the absence of Ddi1, Ho does not form a complex with the 19S RP and is stabilized. Stabilization of Ho leads to perturbation of the cell cycle and to the formation of multi-budded cells. Our experiments uncover a novel role for the ubiquitin-proteasome system in maintenance of genome stability.

[1] UIM = ubiquitin-interacting motif

W. den Besten, M-L. Kuo, K. Tago, R.T. Williams and C.J. Sherr

The Ink4a-Arf locus, which encodes two distinct tumor suppressor proteins, is inactivated in many cancers. Whereas p16Ink4a is an inhibitor of cyclin D-dependent kinases, p19Arf (p14ARF in humans) antagonizes the E3 ubiquitin protein ligase activity of Mdm2 to activate p53. We now recognize that Arf functions in both p53-dependent and -independent modes to counteract hyper-proliferative signals originating from proto-oncogene activation, but its p53-independent activities remain poorly understood. Arf proteins are highly basic (> 20% arginine content, pI > 12) and predominantly localize within nucleoli in physical association with an abundant acidic protein, nucleophosmin (NPM/B23). When bound to NPM[1], Arf proteins are relatively stable with half-lives of 6–8 hours. Although mouse p19Arf contains only a single lysine residue and human p14ARF has none, both proteins are N-terminally ubiquitinated and degraded in proteasomes. Through as yet uncharacterized mechanisms, p19Arf induces p53-independent sumoylation of a variety of cellular target proteins with which it interacts, including both Mdm2 and NPM. A naturally occurring NPM mutant (NPMc) expressed in myeloid leukemia cells redirects both wild-type NPM and p19Arf to the cytoplasm, inhibits Arf-induced sumoylation, and attenuates p53 activity. Thus, ubiquitination and sumoylation can each influence Arf tumor suppressor activity.

[1] NPM = nucleophosmin

Original Articles
D. Bendayan, D. Shitrit and M.R. Kramer

Background: New drugs have significantly improved the prognosis and quality of life of patients with pulmonary arterial hypertension. However, PAH[1] associated with autoimmune disease, particularly progressive sclerosis, remains a very serious problem

Objectives: To evaluate whether the course of the disease and survival is significantly different in patients with PAH related to autoimmune disease as compared to other patients with PAH and to determine the prognostic factors in these patients.

Methods: We retrospectively compared 24 patients with PAH associated with autoimmune disease to 42 patients with other causes of PAH. We focused on the clinical and hemodynamic parameters and on the outcome.

Results: The early mortality rate was slightly higher in patients with PAH associated with autoimmune disease (13% after the first year, 25% after the fifth year). The prognostic factor was a shorter distance on the 6 minutes walking distance test (r = 0.2, P = 0.01).

Conclusions: The early detection of PAH associated with autoimmune disease should encourage earlier and more aggressive treatment than in idiopathic PAH.

[1] PAH = pulmonary arterial hypertension

C. Weissman, L.A. Eidelman, R. Pizov, I. Matot, N. Klein and R. Cohn

Background: Anesthesiology is a vital specialty that permits the safe and humane performance of painful procedures. Most Israeli anesthesiologist are immigrants, while only a minimal number of Israeli medical school graduates enter the specialty. Unfortunately, the supply of immigrant physicians is declining due to falling immigration rates.

Objectives: To examine the current Israeli anesthesiology workforce and project future needs.

Methods: Demographic and professional information about Israeli hospital anesthesiologists was solicited from anesthesiology department heads. Data were also gathered about the past, present and projected future growth, age distribution and birth rate of the Israeli population. Needs and demand-based analyses were used to project future anesthesiology workforce requirements.

Results: Data about 711 anesthesiologists were obtained from 30 hospital anesthesiology department heads. Eighty-seven anesthesiologists (12.2%) graduated from Israeli medical schools and 459 (64.6%) graduated from medical schools in the former Soviet Union. Among the 154 anesthesiology residents were ≤ 40 years old, and only 13 (8.4%) graduated from Israeli medical schools There are approximately 10.8 anesthesiologists per 100,000 population. Projections for 2005–2015 revealed a need for 250–300 new anesthesiologists.
Conclusions: The anesthesiology workforce is predominantly composed of immigrants. This has vast implications for the future viability of the specialty because of the continuing reduction in immigration, the lack of interest in the specialty by Israeli medical school graduates, and the projected need for many new anesthesiologists to replace retirees and to provide care to a growing and aging population

F. Magora, S. Cohen, M. Shochina and E. Dayan

Background: Virtual reality immersion has been advocated as a new effective adjunct to drugs for pain control. The attenuation of pain perception and unpleasantness has been attributed to the patient's attention being diverted from the real, external environment through immersion in a virtual environment transmitted by an interactive 3-D software computer program via a VR[1] helmet.

Objectives: To investigate whether VR immersion can extend the amount of time subjects can tolerate ischemic tourniquet pain.

Methods: The study group comprised 20 healthy adult volunteers. The pain was induced by an inflated blood pressure cuff during two separate, counterbalanced, randomized experimental conditions for each subject: one with VR and the control without VR exposure. The VR equipment consisted of a standard computer, a lightweight helmet and an interactive software game.

Results: Tolerance time to ischemia was significantly longer for VR conditions than for those without (P < 0.001). Visual Analogue Scale (0–10) ratings were recorded for pain intensity, pain unpleasantness, and the time thought about pain. Affective distress ratings of unpleasantness and of time thought about pain were significantly lower during VR as compared with the control condition (P < 0.003 and 0.001 respectively).

Conclusions: The VR method in pain control was shown to be beneficial. The relatively inexpensive equipment will facilitate the use of VR immersion in clinical situations. Future research is necessary to establish the optimal selection of clinical patients appropriate for VR pain therapy and the type of software required according to age, gender, personality, and cultural factors.

[1] VR = virtual reality

O. Bronshtein, V. Katz, T. Freud and R. Peleg

Background: Physicians in the community work on a tight and often pressured schedule; verbal and non-verbal techniques to terminate the patient-physician encounter are therefore necessary.

Objectives: To characterize ways of terminating the encounter.

Methods: Using a structured questionnaire we observed seven family physicians and nine consultants and recorded patient-physician encounters to assess techniques for terminating the encounter.

Results: In all, 320 encounters were recorded, 179 (55.9%) by consultants and 141 (44.1%) by family physicians. The mean duration of the encounters was 9.02 ± 5.34 minutes. The mean duration of encounters with family physicians was longer than consultants (10.39 vs. 7.93 minutes, P < 0.001). In most cases the encounter ended with the patient receiving printed documentation from the physician (no difference between family physicians and consultants). Consultants were more likely to end the encounter with a positive concluding remark such as “feel good” or “be well” (P < 0.01). There was no single occasion where termination of the encounter was initiated by the patient.

Conclusions: Giving a printed document to the patient appears to be perceived by both patients and physicians as an accepted way to end an encounter. Another good way to end the encounter is a positive greeting such as “feel good” or “be well.”

G. Ofer, B. Rosen, M. Greenstein, J. Benbassat, J. Halevy and S. Shapira

Background: Debate continues in Israel as to whether to allow patients in public hospitals to choose their physician in return for an additional, out-of-pocket payment. One argument against this arrangement is that the most senior physicians will devote most of their time to private patients and not be sufficiently available to public patients with complex cases.

Objectives: To analyze the patterns of surgical seniority in Jerusalem hospitals from a number of perspectives, including the extent to which: a) opting for private care increases the likelihood of being treated by a very senior surgeon; b) public patients undergoing complex operations are being treated by very senior surgeons, c) the most senior surgeons allocate a significant portion of their time to private patients.

Methods: Demographic and clinical data were retrieved from the operating room records of three of the public hospitals in Jerusalem for all 38,840 operations performed in 2001. Of them, roughly 6000 operations (16%) were performed privately. Operations were classified as "most complex," "moderately complex" and "least complex" by averaging the independent ratings of eight medical and surgical experts. The surgeon's seniority was graded as "tenured" (tenured board-certified specialists, including department heads), "senior" (non-tenured board-certified specialists), and "residents." For each operation, we considered the seniority of the lead surgeon and of the most senior surgeon on the surgical team.

Results: The lead surgeon was of tenured rank in 99% of the most complex private cases and 74% of the most complex public cases, in 93% of the moderately complex private and 35% of the moderately complex public cases, and in 92% of the least complex private and 32% of the least complex public cases. The surgical team included a tenured physician in 97%, 66%, and 53% of the most complex, moderately complex, and least complex public operations, respectively. In both private and public cases, a board-certified (tenured or senior) specialist was a member of the surgical team for almost all of the most complex and moderately complex operations. On average, over half of the operations in which the lead surgeon was a department head were performed on public patients. Among tenured surgeons, those who spent more hours than their colleagues leading private operations also tended, on average, to spend more hours leading public operations.

Conclusions: Private patients have an advantage over public patients in terms of the seniority of the lead surgeon. However, there is also substantial involvement of very senior surgeons in the treatment of public patients, particularly in those cases that are most complex. 

Stem Cell Research
I.M. Barbash and J. Leor

Ventricular remodeling and heart failure are the inevitable consequences of myocardial infarction. Current options to cure myocardial infarction and subsequent heart failure suffer from specific limitations. Thus, alternative, additional long-term therapeutic strategies are needed to cure this costly and deadly disease. Cardiac regeneration is a promising new therapeutic option. Through cellular and molecular therapies, the concept of in situ "growing" heart muscle, vascular tissue and manipulating the extracellular matrix environment promises to revolutionize the approach of treating heart disease. Recent studies have suggested that stem cells resident within the bone marrow or peripheral blood can be recruited to the injured heart. The regeneration of damaged heart tissue may include the mobilization of progenitor or stem cells to the damaged area or stimulation of a regenerative program within the organ. There is now evidence accumulating that the heart contains resident stem cells that can be induced to develop into cardiac muscle and vascular tissue. The present review aims to describe the potential, the current status and the future challenges of myocardial regeneration by adult stem cells.


Case Communication
H. Mazeh, A. Nissan, N. Simanovsky and N. Hiller
E. Miller, Y. Barnea, A. Karin, D. Leshem, J. Weiss, L. Leider-Trejo and S. Schneebaum
U. Abadi, R. Hadary, L.Shilo, A. Shabun, G. Greenberg and S. Kovatz
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