Cyclooxygenase-2 (COX-2), which acts in many pathological states as the rate limiting enzyme in prostaglandins biosynthesis, is proposed to promote tumor progression at several stages. Prostaglandins apparently not only drive the initial formation of certain pre-cancerous lesions, but also support the development of blood vessels that permit tumor growth and the phenotypic changes that result in metastasis. Much of the analysis of COX-2 regulation has focused on transcriptional control, but Dixon and coworkers now show that post-transcriptional effects may be equally important. The COX-2 mRNA, like other gene products that require rapid induction and repression, carries an A/U-rich element (ARE), a cis-acting RNA-destabilizing sequence. Dixon et al. compared the expression of this mRNA in two different human colon carcinoma cell lines, and they report here that the more aggressively tumorigenic line, HT29, expresses greatly elevated levels of the COX-2 message relative to the slower growing LoVo cell line. This difference can be ascribed to an increase in mRNA stability, not an increase in transcription rate; on the contrary, the COX2 promoter is far more active in the cells with low steady-state levels of COX-2 mRNA. Dixon et al. attribute the specific stabilization of the message to the expression of the RNA-binding protein HuR, which interacts specifically with AREs of the type found in the COX-2 sequence. Overexpression of HuR in LoVo cells increases COX2 mRNA levels as well as increasing the synthesis of prostaglandins and two pro-angiogenic factors whose expression is associated with COX activity. This work suggests the interesting possibility that activation of HuR or other specific regulators of mRNA decay occurs during multistage tumorigenesis.

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Contact: John Ashkenas
scied@the-jci.org
416-946-7593
Journal of Clinical Investigation
28-Nov-2001

Page: 1
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