In a new study, researchers reveal how a key player in cell growth, immunity and the inflammatory response can be transformed into a primary contributor to tumour growth.
\nScientists call this Jekyll-and-Hyde molecule NF-kappa B. In healthy cells, it is a powerful ‘first responder,’ a vital part of the body\u2019s immune and inflammatory responses. It spends most of its life in the cell\u2019s cytoplasm, quietly awaiting orders. But when extracellular signals \u2013 of a viral or bacterial invasion, for example \u2013 set off chemical alarms, the cell unchains this warhorse, allowing it to go into the nucleus where it spurs a flurry of defensive activity, including the transcription of genes that trigger inflammation, promote cell proliferation and undermine cell death.
\nResearchers have known for years that a hyperactive form of NF-kappa B that gets into the nucleus and stays there is associated with various cancers. But they didn\u2019t know what was keeping it active in the nucleus.
\n‘Normally in the cell NF-kappa B is in the cytosol, it\u2019s not in the nucleus, and it\u2019s not activated,’ said University of Illinois medical biochemistry professor Lin-Feng Chen, who led the new study. ‘You have to stimulate normal cells to see NF-kappa B in the nucleus. But in cancer cells without any stimulation you can see this nuclear form of NF-kappa B. The cell just won\u2019t die because of this. That is why NF-kappa B is so important in cancer.’
\nIn the new study, Chen\u2019s group found that another molecule known to help regulate gene expression, called BRD4, recognises a specific amino acid on a subunit of the NF-kappa B protein complex after the amino acid has been marked with a specific tag, called an acetyl group. This ‘acetylation’ allows the BRD4 to bind to NF-kappa B, activating it and preventing its degradation in cancer cells.
\nPrevious studies had shown that BRD4\u2019s recognition of the acetylated subunit increased NF-kappa B activation, but this recognition had not been linked to cancer.
\nBRD4 belongs to a class of molecules that can recognise chemical markers on other proteins and interact with them to spur the marked proteins to perform new tasks. Chemical ‘readers’ such as BRD4 are important players in the field of epigenetics, which focuses on how specific genes are regulated.
\n‘In epigenetics, there are writers, there are readers and there are erasers,’ Chen said. The writers make modifications to proteins after they are formed, without changing the underlying sequence of the gene that codes for them. These modifications (such as acetylation) signal other molecules (the readers) to engage with the marked proteins in various ways, allowing the proteins to fulfill new roles in the life of the cell. Epigenetic erasers remove the marks when they are no longer of use.
\nSuch protein modifications ‘have been shown to be critically involved in transcription regulation and cancer development,’ the researchers report.
\nTo test whether BRD4 was contributing to the sustained presence of NF-kappa B in the nucleus of cancer cells, Chen and his colleagues exposed lung cancer cells in cell culture and in immune-deficient mice to JQ1, a drug that interferes with BRD4 activity. Exposure to JQ1 blocked the interaction of BRD4 and NF-kappa B, blocked the expression of genes regulated by NF-kappa B, reduced proliferation of lung cancer cells and suppressed the ability of lung cancer cells to induce tumors in immune-deficient mice, the researchers found.
\nThe researchers also discovered that depletion of BRD4 or the treatment of cells with JQ1 induced the degradation of the NF-kappa B subunit recognized by BRD4.
\nChen said that BRD4 likely prevents other molecules from recognising the hyperactive NF-kappa B in the nucleus and marking it for degradation.
\n‘This is an example of how epigenetic regulators and NF-kappa B may one day be targeted for the treatment of cancer,’ he said.\nUniversity of Illinois at Urbana Champaign<\/link>\n","protected":false},"excerpt":{"rendered":"
In a new study, researchers reveal how a key player in cell growth, immunity and the inflammatory response can be transformed into a primary contributor to tumour growth. Scientists call this Jekyll-and-Hyde molecule NF-kappa B. In healthy cells, it is a powerful ‘first responder,’ a vital part of the body\u2019s immune and inflammatory responses. It […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[35],"tags":[],"_links":{"self":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/1859"}],"collection":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/comments?post=1859"}],"version-history":[{"count":0,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/1859\/revisions"}],"wp:attachment":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/media?parent=1859"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/categories?post=1859"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/tags?post=1859"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}