Novel insights into the mechanisms of regulation of tyrosine kinase receptors by Ras Interference 1

Receptor-tyrosine kinases (RTKs) are membrane bound receptors characterized by their intrinsic kinase activity. RTK activities play an essential role in several human diseases, including cancer, diabetes and neurodegenerative diseases. RTK activities have been regulated by the expression or silencing of several genes as well as by the utilization of small molecules. Ras Interference 1 (Rin1) is a multifunctional protein that becomes associated with activated RTKs upon ligand stimulation. Rin1 plays a key role in receptor internalization and in signal transduction via activation of Rab5 and association with active form of Ras. This study has two main objectives: (1) It determines the role of Rin1 in the regulation of several RTKs focusing on insulin receptor. This was accomplished by studying the Rin1-insulin receptor interaction using a variety of biochemical and morphological assays. This study shows a novel interaction between the insulin receptor and Rin1 through the Vps9 domain. Two more RTKs (epidermal growth factor receptor and nerve growth factor receptor) also interacted with the SH2 domain of Rin1. The effect of the Rin1-RTK interaction on the activation of both Rab5 and Ras was also studied during receptor internalization and intracellular signaling. Finally, the role of Rin1 was examined in two differentiation processes (adipogenesis and neurogenesis). Rin1 showed a strong inhibitory effect on 3T3-L1 preadipocyte differentiation but it seems to show a modest effect in PC12 neurite outgrowth. These data indicate a selective function and specific interaction of Rin1 toward RTKs. (2) It examines the role of the small molecule Dehydroleucodine (DhL) on several key signaling molecules during adipogenesis. This was accomplished by studying the differentiation of 3T3-L1 preadipocytes exposed to different concentrations of DhL in different days of the adipocyte formation process. The results indicate that DhL selectively blocked adipocyte formation, as well as the expression of PPARγ, and C/EBP&agr;. However, DhL treatment did not affect Rin1 or Rab5 expression and their activities. Taken together, the data indicate a potential molecular mechanism by which proteins or small molecules regulate selective and specific RTK intracellular membrane trafficking and signaling during cell growth and differentiation in normal and pathological conditions.

Regulating Casino Gaming: A Checklist for States Considering It

In his essay - Regulating Casino Gaming: A Checklist for States Considering It – by Leonard E. Goodall, Professor of Management and Public Administration, College of Business and Econornics, University of Nevada, Las Vegas, Professor Goodall initially states: “Since various states are likely to continue to debate the issue of the establishment of legal casinos, and since states considering legal casinos must also decide how best to regulate them, the author discusses the similarities and contrasts in the regulatory systems already in operation.” Certainly not all states have solicited casino gaming, or what people generally refer to as gambling, but many have and the list is growing. If casinos are to be, and indications are that many more states will endorse gaming as a source of revenue, then regulating them must follow as a matter of due course says the author. Keep in mind this essay was written in 1988, and the actuality of casino gaming has indeed come to fruition in many states. “Nevada, having legalized casino gaming in 1931, has over a half-century of experience with the regulatory process,” Professor Goodall informs. “When New Jersey approved the establishment of casinos in Atlantic City in 1976, state officials studied the Nevada system carefully and adopted many of Nevada's procedures.” Professor Goodall bullet-points at least 7 key elements that states wanting to pursue gaming should, or in the cases of Nevada and New Jersey, have already addressed in regard to regulation of the industry. Goodall parses, in more detail, those essentials. The ultimate form of regulation is ownership Goodall says. Either state run, or private are the logical options. “The arguments for private ownership have been both pragmatic and political,” Goodall says. “Legislators, like the general public, are skeptical of the ability of state bureaucracies to run big businesses in an efficient manner. Many of them also believe regulation can be more effective if there is at least an arm's-length distance between regulation and ownership,” the professor opines. Additionally important to consider is the purpose of legalization, says Goodall. Are the proceeds earmarked for general funds, or to be used specifically? Geographic considerations are key, Goodall points out. “This decision will depend partly on a state's reasons for having casinos in the first place,” he expands. “New Jersey's policy, for example, is obviously consistent with its goal of using casinos to reinvigorate Atlantic City.” “In both states, one of the most important functions of the regulatory agencies is that of licensing, the process of investigating individuals or organizations and then authorizing them to participate in the gaming business,” Goodall provides. In closing, Goodall says there is no need for ensuing states to reinvent the wheel when it comes to casino gaming regulation. Nevada and New Jersey already provide two good designs from which to emulate and/or build upon.

Essays on financial crises

This dissertation analyzes recent financial crises in developed and developing countries. The research emphasizes the effects of institutional factors on the international banking and currency crises and their output losses. ^ Chapter two examines the roles of regulation, supervision, and countries' institutional environment in determining the probability of banking crises for a panel of fifteen developed countries from 1975 to 1998. The results from a multivariate logit model indicated that countries with greater government involvement, less capital standard requirements, and lower lending limits on a single borrower are associated with a higher probability of banking crises. ^ Chapter three studies whether output loss in banking crisis differs in market-based or bank-based financial systems. Using existing banking crisis data for sixty-nine countries during 1970–1999, we investigate whether the underlying financial system affects the output loss. The results show that output losses are more serious in market-based economies than those in bank-based economies. Longer crisis duration tends to increase the output losses in banking crises. Finally, countries with deposit insurance and strict law enforcement have less output losses. ^ Chapter four uses macroeconomic and institutional measures to explain the extent of exchange rate depreciation and the decline in stock prices for emerging countries affected by the Mexican currency crisis of 1994–95. The results show that countries with more government budget deficits, and worse reserve adequacies tend to experience large exchange rate depreciation. The institutional measures do not explain much the extent of both the exchange rate depreciation and the decline in stock prices. ^