4. Department of Pharmacological Sciences, Stony Brook Medicine, Stony Brook, New York.
Abstract
Keratins that are overexpressed selectively in human carcinomas may offer diagnostic and prognostic utility. In this study, we show that high expression of keratin-17 (K17) predicts poor outcome in patients with cervical cancer, at early or late stages of disease, surpassing in accuracy either tumor staging or loss of p27KIP1 as a negative prognostic marker in this setting. We investigated the mechanistic basis for the biologic impact of K17 through loss- and gain-of-function experiments in human cervix, breast, and pancreatic cancer cells. Specifically, we determined that K17 functions as an oncoprotein by regulating the subcellular localization and degradation of p27KIP1. We found that K17 was released from intermediate filaments and translocated into the nucleus via a nuclear localization signal (NLS), specific among keratins, where it bound p27KIP1 during G1 phase of the cell cycle. p27KIP1 lacks a nuclear export signal (NES) and requires an adaptor for CRM1 binding for nuclear export. In K17, we defined and validated a leucine-rich NES that mediated CRM1 binding for export. Cervical cancer cells expressing K17 mutations in its NLS or NES signals exhibited an increase in levels of nuclear p27KIP1, whereas cells expressing wild-type K17 exhibited a depletion in total endogenous p27KIP1. In clinical specimens of cervical cancer, we confirmed that the expressions of K17 and p27KIP1 were inversely correlated, both across tumors and within individual tumors. Overall, our findings establish that K17 functions specially among keratins as an oncoprotein by controlling the ability of p27KIP1 to influence cervical cancer pathogenesis. Cancer Res; 75(17); 3650–62. ©2015 AACR.

9. KJ Immunology How farm life prevents asthma
Science 4 September 2015: Vol. 349 no p DOI: /science
In Depth
Immunology
How farm life prevents asthma
Jocelyn Kaiser
Researchers have homed in an explanation for an intriguing observation: Children who grow up on dairy farms are much less likely than the average child to develop asthma. A European team reports that bits of bacteria found in farm dust trigger an inflammatory response in the animals' lungs that later protects them from this respiratory disease. An enzyme involved in this defense is sometimes disabled in people with asthma, suggesting that treatments inspired by this molecule could ward off the condition in people. The study, published on page 1106, offers new support for the so-called hygiene hypothesis, a 26-year-old idea that posits that our modern zeal for cleanliness and widespread use of antibiotics have purged the environment of microorganisms that once taught a child's developing immune system not to overreact to foreign substances.

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