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The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer (1) and T-cell acute lymphoblastic leukaemia (T-ALL) (2). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL (3-5), validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun (6), Myc (7), cyclin E (8) and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth (10), overexpression of Jun, Myc or notch 1 can also induce programmed cell death (11). Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Mbc and/or notch 1. Here we show that the E3 ubiquitin ligase [SCF.sup.FBW7] (a SKP1-cullin-1-F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7-deficient T-ALL., MCL1 is frequently overexpressed in various leukaemias through mechanisms that are not fully understood (12). MCL1 is distinct from other BCL2 family members in its extremely unstable nature (13), which [...]

This study compared high level managerial jobs in public and private sectors. Results indicate that managers in the public sector perform the same kind of activities as managers in the private sector in terms of complexity of job content and roles and in terms of job characteristics. (Author)

The management of research and development activities in both the public and private sectors is compared to the management of other organizational areas. A survey of 448 managers indicates that research and development managers view their roles in much the same manner as other managers. In addition, the research indicates that managerial roles are assigned similar levels of importance by managers in both private industry and governmental work.

Fbw7 and Cdh1 are substrate-recognition subunits of the SCF- and APC-type E3 ubiquitin ligases, respectively. There is emerging evidence suggesting that both Fbw7 and Cdh1 function as tumor suppressors by targeting oncoproteins for destruction. Loss of Fbw7, but not Cdh1, is frequently observed in various human tumors. However, it remains largely unknown how Fbw7 mechanistically functions as a tumor suppressor and whether there is a signaling crosstalk between Fbw7 and Cdh1. Here, we report that Fbw7-deficient cells not only display elevated expression levels of SCFFbw7 substrates, including cyclin E, but also have increased expression of various APCCdh1 substrates. We further defined cyclin E as the critical signaling link by which Fbw7 governs APCCdh1 activity, as depletion of cyclin E in Fbw7-deficient cells results in decreased expression of APCCdh1 substrates to levels comparable to those in wild-type (WT) cells. Conversely, ectopic expression of cyclin E recapitulates the aberrant APCCdh1 substrate expression observed in Fbw7-deficient cells. More importantly, 4A-Cdh1 that is resistant to Cdk2/cyclin E-mediated phosphorylation, but not WT-Cdh1, reversed the elevated expression of various APCCdh1 substrates in Fbw7-deficient cells. Overexpression of 4A-Cdh1 also resulted in retarded cell growth and decreased anchorage-independent colony formation. Altogether, we have identified a novel regulatory mechanism by which Fbw7 governs Cdh1 activity in a cyclin E-dependent manner. As a result, loss of Fbw7 can lead to aberrant increase in the expression of both SCFFbw7 and APCCdh1 substrates. Our study provides a better understanding of the tumor suppressor function of Fbw7, and suggests that Cdk2/cyclin E inhibitors could serve as effective therapeutic agents for treating Fbw7-deficient tumors. [ABSTRACT FROM AUTHOR]

Summary: The NFκB/Rel family of proteins play critical roles in a variety of cellular processes. Thus, their physiological activation is tightly controlled. Recently, the NFκB2/p100 precursor has been characterized as the fourth IκB type of suppressor for NFκB. However, the molecular mechanism(s) underlying regulated destruction of NFκB2 remains largely unknown. Here, we report that, unlike other IκBs, ubiquitination and destruction of NFκB2 are governed by SCFFbw7 in a GSK3-dependent manner. In Fbw7−/− cells, elevated expression of NFκB2/p100 leads to a subsequent reduction in NFκB signaling pathways and elevated sensitivity to TNFα-induced cell death. Reintroducing wild-type Fbw7, but not disease-derived mutant forms of Fbw7, rescues NFκB activity. Furthermore, T cell-specific depletion of Fbw7 also leads to reduced NFκB activity and perturbed T cell differentiation. Therefore, our work identifies Fbw7 as a physiological E3 ligase controlling NFκB2′s stability. It further implicates that Fbw7 might exert its tumor-suppressor function by regulating NFκB activity. [ABSTRACT FROM AUTHOR]

NF-κB/Rel is a family of transcription factors which are expressed in all cells; however, in most non-B cells, they are sequestered in the cytoplasm in inactive complexes with specific inhibitory proteins, termed IκBs. We have recently shown that NF-κB/Rel factors are aberrantly activated in human breast cancer and rodent mammary tumors, and function to promote tumor cell survival and proliferation. Here, we have examined the time-course of induction of NF-κB/Rel factors upon carcinogen treatment of female Sprague–Dawley (S–D) rats in vivo and in human mammary epithelial cells (HMECs) in culture. We observed that NF-κB/Rel activation is an early event, occurring prior to malignant transformation. In S–D rats, increased NF-κB/Rel binding was detected in nuclear extracts of mammary glands from 40% of animals 3 weeks post-treatment with 15 mg/kg 7,12-dimethylbenz[a]anthracene (DMBA); this is prior to formation of tumors which normally begin to be detected after 7–9 weeks. In non-tumorigenic MCF-10F cells, in vitro malignant transformation upon treatment with either DMBA or benzo[a]pyrene (B[a]P) resulted in a 4- to 12-fold increase in activity of classical NF-κB (p65/p50). NF-κB induction was corrrelated with a decrease in the stability of the NF-κB-specific inhibitory protein IκB-α. Ectopic expression of the transactivating p65 subunit of NF-κB in MCF-10F cells induced the c-myc oncogene promoter, which is driven by two NF-κB elements, and endogenous c-Myc levels. Furthermore, reduction mammoplasty-derived HMECs, immortalized following B[a]P exposure, showed dysregulated induction of classical NF-κB prior to malignant transformation. Together these findings suggest that activation of NF-κB plays an early, critical role in the carcinogen-driven transformation of mammary glands. [ABSTRACT FROM PUBLISHER]

Subjects were drilled and tested on their ability to judge sonar Doppler. Synthetic sonar echoes were systematically varied with respect to type of Doppler, echo duration, the rate of echo onset, and relative signal strength, and superimposed upon a sea-recorded reverberation pattern. The purposes of the study were to (1) identify the effects that variations in echo length, echo onset, and relative signal strength have upon the ability to discriminate Doppler correctly; and (2) evaluate the effect that training has upon the improvement of Doppler discrimination. Results indicated that performance was significantly improved by training. Although Doppler discrimination was significantly affected by echo duration and the relative intensity of the echo, the interactions among the echo dimensions appeared to be largely the result of various perceptual or response biases toward no Doppler echoes. [ABSTRACT FROM AUTHOR]

Loss of the Fbw7 tumor suppressor is common in diverse human cancer types, including T-Cell Acute Lymphoblastic Leukemia (T-ALL), although the mechanistic basis of its anti-oncogenic activity remains largely unclear. We recently reported that SCF\(^{Fbw7}\) regulates cellular apoptosis by controlling the ubiquitination and destruction of the pro-survival protein, Mcl-1, in a GSK3 phosphorylation-dependent manner. We found that human T-ALL cell lines displayed a close relationship between Fbw7 loss and Mcl-1 overexpression. More interestingly, T-ALL cell lines that are deficient in Fbw7 are particularly sensitive to sorafenib, a multi-kinase inhibitor that has been demonstrated to reduce Mcl-1 expression through an unknown mechanism. On the other hand, Fbw7-deficient T-ALL cell lines are much more resistant to the Bcl-2 antagonist, ABT-737. Furthermore, reconstitution of Fbw7 or depletion of Mcl-1 in Fbw7-deficient cells restores ABT-737 sensitivity, suggesting that elevated Mcl-1 expression is important for Fbw7-deficient cells to evade apoptosis. Therefore, our work provides a novel molecular mechanism for the tumor suppression function of Fbw7. Furthermore, it provides the rationale for targeted usage of Mcl-1 antagonists to treat Fbw7-deficient T-ALL patients.