A new way to suppress apoptosis?

A chromosomal protein appears to help deactivate cell growth regulator p53

By | February 9, 2007

In what may be a new mechanism cells use to suppress apoptosis, overexpression of a chromosomal protein appears to inactivate p53, according to a new study appearing this week in the Journal of Clinical Investigation. The researchers found that overexpression of the high mobility group protein A1 (HMGA1) appears to deactivate the tumor suppressor gene p53 by shuttling its activator protein out of the nucleus in cancer cells. "This paper identifies a new potential mechanism of [p53 inactivation]," Gerard Evan, a cancer biologist at the University of California San Francisco who was not involved in the current research, told The Scientist. Mutations in p53, a transcription factor, have been associated with more than 50 percent of all human tumors. P53 regulates cell growth by apoptosis, and can shrink tumors when reactivated. The study was led by a group at the Istituto Nazionale dei Tumori Regina Elena in Rome, whose previous work concentrated on the relationship between HMGA1, p53 and homeodomain-interacting protein kinase 2(HIPK2), one of the many activating kinases for p53. "We started from the observation that HMGA1 combines in vitro with both HIPK2 and p53," Silvia Soddu, the senior author of the study, told The Scientist. "But we didn't know the meaning of all these interactions." Having first thought that all three proteins were working on gene transcription in tandem, the group recognized that, with a higher ratio of HMGA1 (relative to HIPK2) in cell lines, HIPK2 appeared in the cytoplasm. The group then designed their experiment to model the effect that overexpression of HMGA1 would have on HIPK2, and subsequently, p53 activation. In a series of in vitro experiments, the group transfected cells with either HMGA1 or HIPK2, then monitored protein activity levels, including the action of p53. They found that HMGA1 and HIPK2 had an inverse relationship -- as in, more of one decreased the amount of the other. In addition, overexpression of HMGA1 kicked HIPK2 out of the nucleus and into the cytoplasm, while an overexpression of HIPK2 diminished HMGA1 levels and reactivated p53. To test whether HMGA1 overexpression had the same "kicking out" power over HIPK2 in actual carcinoma cells, they examined the interaction of these proteins in human breast cancer cells that expressed wild type p53. In those samples, there was a strong correlation between high HMGA1 levels and low rates of apoptosis, suggesting that dumping HIPK2 from the nucleus inactivated p53. "It's certainly a plausible mechanism, but its relevance to normal pathology is still rather circumstantial," noted UCSF's Evan. Hua Lu, a p53 researcher at the Vollum Institute in Oregon who was also not a co-author, agreed that the findings are preliminary. "They're not examining the endogenous protein, in the nucleus. They're just examining something they put into the cell," Lu told The Scientist. Lu added that the researchers examined the breast cancer samples for p53 activity by immunostaining, rather than explicitly testing for p53 action, a shortcut that may impact their conclusions. Overexpressing one protein or another also creates certain limitations, Lu noted. As opposed to "knocking out" one protein by genetically altering the cells and then observing the action of the other proteins, overexpressing one or more proteins doesn't give the full picture of the holistic relationship in the cell, or exclude other possible mechanisms. For instance, cells may reduce apoptosis via HIPK2, which could "phosphorylate HMGA1 and suppress its function toward p53," Lu noted -- a finding that, if confirmed, would belie the mechanism Soddu and her colleagues propose, he added. Andrea Gawrylewski mail@the-scientist.com Links within this story ML Phillips, "Cell death unnecessary for tumor suppression," The Scientist, September 6, 2006. http://www.the-scientist.com/news/display/24625/ Gerard Evan http://cancer.ucsf.edu/evan/index.php JM Perkel, "Tumors shrink when p53 restored," The Scientist, January 24, 2007. http://www.the-scientist.com/news/display/43281/ GM Pierantoni et al, "High Mobility Group A1 (HMGA1) proteins interact with p53 and inhibit its apoptotic activity" Cell Death and Differentiation, September, 2006. http://www.the-scientist.com/pubmed/16341121 B Cecchinelli et al, "Ser58 of mouse p53 is the homologue of human Ser46 and is phosphorylated by HIPK2 in apoptosis," Cell Death and Differentiation, November, 2006. http://www.the-scientist.com/pubmed/16729035 JM Perkel, "How to detect apoptosis," The Scientist, April 1, 2006. http://www.the-scientist.com/article/display/23308

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