Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lactoferrin, a member of the transferrin family, is iron-binding and a strongly cationic 76 kDa glycoprotein. In breast milk it is secreted in high concentrations from glandular epithelia and is also present in other exocrine fluids including saliva. In the present study, we examined the biological mechanisms of apoptosis induced by pepsin-digested-lactoferrin peptide (Lfn-p) in the human oral squamous cell carcinoma cell line SAS. We found that treatment with Lfn-p induced cell death with apoptotic nuclear changes, preceded by the cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in the apoptotic cells. Treatment with Lfn-p induced phosphorylation of extracellular signal-regulated kinase (ERK1/2), a member of the MAP kinase family, at early stages of apoptosis. Another MAP kinase, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), was also phosphorylated by treatment with Lfn-p. Pretreatment of SAS cells with SP600125, a JNK/SAPK inhibitor, diminished Lfn-induced apoptosis, as assessed by determining released lactate dehydrogenase activity. On the other hand, the MEK1 inhibitors PD98059 or U0126 showed no effect on repression of cell death, but rather an increase. These results suggest that JNK/SAPK activation may play an important role in Lfn-p-induced apoptotic cell death of human oral squamous cell carcinoma cells.
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PMID:Pepsin-digested bovine lactoferrin induces apoptotic cell death with JNK/SAPK activation in oral cancer cells. 1587 78

The metalloprotease lethal factor (LF) from Bacillus anthracis plays a vital role in anthrax toxin action, and thus becomes a target for anti-anthrax therapy. Following the guidelines based on existing metalloprotease inhibitors, we designed a 'first-generation' LF inhibitor R9LF-1. This inhibitor was shown to be very stable by itself in a wide range of pH and temperature and able to inhibit LF activity in vitro. However, as we reported previously in the presence of LF, this inhibitor was degraded to a small molecular weight species, resulting in a significantly decreased ability to protect MAPKK from cleavage by LF as well as to protect murine macrophages from lethal toxin. In order to elucidate this unusual phenomenon to build solid basis for high-efficiency LF inhibitor development, we performed extensive research to study the effect of LF on its peptide-based inhibitor. Effects of temperature and incubation period of time on generation of the smaller peptide (short version R9LF-1) by LF as well as its catalytic domain were analyzed. We found that LF degraded R9LF-1 with maximum efficiency in the pH range of 7.0-8.5, which correlates well with the range of LF enzymatic activity with its native substrate. The degradation showed a deviation from normal hyperbolic kinetics but a similarity to the kinetics profile of an enzyme-catalyzed reaction with positive cooperativity. The short version R9LF-1 had decreased inhibitory activity toward LF; surprisingly, BIAcore results suggested a better affinity for its binding to LF. In addition, R9LF-1 was not hydrolyzed by other common proteases, such as chymotrypsin and pepsin, suggesting hydrolysis of the bond between amino acid and hydroxamate groups is unique to LF. This study calls for caution when designing peptide-based LF inhibitors and when interpreting effects of these types of inhibitors.
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PMID:Effects of metalloprotease anthrax lethal factor on its peptide-based inhibitor R9LF-1. 2598 34