The recent FDA approval of two drugs to treat the basic defect in cystic fibrosis has given hope to patients and their families battling this devastating disease. Over many years, with heavy financial investment from Vertex Pharmaceuticals and the Cystic Fibrosis Foundation, pre-clinical evaluation of thousands of synthetic drugs resulted in the production of Kalydeco and Orkambi. Yet, despite the success of this endeavor, many other compounds have been proposed as therapeutic agents in the treatment of CF. Of note, several of these compounds are naturally occurring, and are present in spices from the grocery store and over the counter preparations in health food stores. In this short review, we look at three such compounds, genistein, curcumin, and resveratrol, and evaluate the scientific support for their use as therapeutic agents in the treatment of patients with CF.

Progression into mitosis is a major point of regulation in the Schizosaccharomyces pombe cell cycle, and its proper control is essential for maintenance of genomic stability. Investigation of the G 2 /M progression event in S. pombe has revealed the existence of a complex regulatory process that is responsible for making the decision to enter mitosis. Newer aspects of this regulation are still being revealed. In this paper, we report the discovery of a novel mode of regulation of G 2 /M progression in S. pombe. We show that the mitogen-activated protein kinase (MAPK)-regulated transcription factor Atf1 is a regulator of Cdc13 (mitotic cyclin) transcription and is therefore a prominent player in the regulation of mitosis in S. pombe. We have used genetic approaches to study the effect of overexpression or deletion of Atf1 on the cell length and G 2 /M progression of S. pombe cells. Our results clearly show that Atf1 overexpression accelerates mitosis, leading to an accumulation of cells with shorter lengths. The previously known major regulators of entry into mitosis are the Cdc25 phosphatase and the Wee1 kinase, which modulate cyclin-dependent kinase (CDK) activity. The significantly striking aspect of our discovery is that Atf1-mediated G 2 /M progression is independent of both Cdc25 and Wee1. We have shown that Atf1 binds to the Cdc13 promoter, leading to activation of Cdc13 expression. This leads to enhanced nuclear localization of CDK Cdc2, thereby promoting the G 2 /M transition. The mammalian basic leucine zipper domain (bZIP) family transcription factor ATF2 is known to be associated with multiple cellular processes, including stress responses, DNA damage responses, and cell cycle regulation. Schizosaccharomyces pombe has a well-characterized ATF2 homolog (Atf1) with functions similar to those of the human ATF2 protein (1-4). It is important for heterochromatin formation and meiotic recombination. Atf1 has also been shown to influence some very important events during S. pombe cell division. In S. pombe, Atf1 was first isolated as the suppressor of the ⌬spc1 phenotype (1). Spc1 is the major mitogenactivated protein kinase (MAPK) in S. pombe and is the homolog of mammalian p38MAPK. It has also been implicated at many important stages of cell cycle control in S. pombe. Atf1 is known to be associated with activation of the spindle orientation checkpoint (5) that controls the metaphase-to-anaphase transition and activation of the anaphase-promoting complex (APC) leading to mitotic exit. It has a synthetic lethal interaction with Cut1 (6). Atf1 is also necessary for accumulation of cells in G 1 after nitrogen starvation (1). It has been shown to be important for degradation of the mitotic cyclin Cdc13 by activating the APC/cyclosome (APC/C) ubiquitin ligase (7).The major point of regulation of the S. pombe cell cycle is the transition from G 2 phase into mitosis. This transition is dependent on the activity of the cyclin-dependent kinase (CDK) Cdc2. The known important regulators of Cdc2 activity in S. pombe a...

Regulatory elements present in the promoter of a gene drive the expression of the gene in response to various stimuli. Lemur Tyrosine Kinase 2 (LMTK2) is a membrane-anchored Serine/Threonine kinase involved in endosomal protein trafficking and androgen signaling amongst other processes. Previous studies have shown this protein to be of therapeutic importance in cystic fibrosis and prostate cancer. However, nothing is known about the endogenous expression of this protein and its regulation. In this study, we analyzed the gene encoding human LMTK2, to look for possible regulatory elements that could affect its expression. Interestingly, the human lmtk2 gene contains a consensus TPA (12- O-Tetradecanoylphorbol-13-acetate)-responsive element (TRE) in the region preceding its start codon. The element with the sequence TGAGTCA modulates LMTK2 expression in response to treatment with TPA, a synthetic Protein Kinase C (PKC) activator. It serves as the binding site for c-Fos, a member of the Activator Protein −1 (AP-1) transcription factor complex, which is transactivated by PKC. We observed that TPA, at low concentrations, increases the promoter activity of LMTK2, which leads to a subsequent increase in the mRNA transcript and protein levels. This modulation occurs through binding of the AP-1 transcription factor complex to the lmtk2 promoter. Thus, our current study has established LMTK2 as a TPA-responsive element-containing gene, which is upregulated downstream of PKC activation. Considering the involvement of LMTK2 in intracellular processes as well as pathological conditions, our findings demonstrate a way to modulate intracellular LMTK2 levels pharmacologically for potentially therapeutic purposes.

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