Sci. Aging Knowl. Environ., 22 January 2003
Vol. 2003, Issue 3, p. nw11
[DOI: 10.1126/sageke.2003.3.nw11]


Parc'n Brake

Relative of Parkinson's protein impounds p53 in the cytoplasm

R. John Davenport;2003/3/nw11

Key Words: Mdm2 • ubiquitin ligase • Cullin

p53 is constantly on the go. The tumor-squelching protein commutes between a cell's cytoplasm and nucleus, where it does its job. Now, scientists have nabbed a protein that might retain p53 in the cytoplasm. The study identifies a potential new regulator of p53 and suggests one way that cells can turn cancerous without having mutations in the p53 gene.

When DNA incurs damage, p53 steps up. Cells activate the protein and send it to the nucleus, where it turns on genes that halt cell division or, if the damage is too severe, trigger cell death. Without p53, genetic havoc goes unchecked and cancer can result: Most human tumors carry crippling mutations in the p53 gene. Some tumors contain normal p53, but they keep the protein sequestered in the cytoplasm, effectively inactivating it.

Nikolaev and colleagues looked for proteins that might trap p53 in the cytoplasm. They engineered human lung cancer cells to manufacture p53 with a short protein tag on one end, isolated cytoplasm from the cells, and pulled out p53 using an antibody that grabs the tag. They found a protein that had hitched a ride. Sequence analysis revealed that it resembles Parkin, a protein implicated in inherited Parkinson's disease (see "Dumpster Diving" and Andersen Review). The group named the new protein Parc. Additional experiments confirmed that Parc tightly grips p53 in the cytoplasm--but not the nucleus--of cultured cells, as well as in the test tube.

The team members then varied the amount of Parc in cells and tracked p53's location. Compared with controls, cells with small concentrations of Parc carried more p53 in their nuclei, whereas cells with extra Parc held more in the cytoplasm; the total quantity of p53 did not change. In addition, about 50% of cells with reduced amounts of Parc killed themselves and cells with normal amounts did not. Together, the results suggest that Parc regulates p53 by confining the protein to the cytoplasm. Further experiments hint that altered Parc function abets some cancers. According to previous work, neuroblastoma cancer cells carry p53 in the cytoplasm at all times and can't respond properly to DNA damage. The researchers found that the tumor cells carried more Parc than normal brain cells did. When they lowered cellular Parc concentrations, p53 flocked to the nucleus. The alteration also restored the cells' ability to commit suicide in response to chemicals that damage DNA.

The study is "compelling," says cancer researcher Michael Clarke of the University of Michigan, Ann Arbor. "If [the work] holds up, the data suggest that this is the pivotal player for anchoring p53 in the cytoplasm." But cancer researcher Jayne Stommel of the Salk Institute for Biological Studies in La Jolla, California, says that some cancer cells have lots of cytoplasmic p53 because they export it from the nucleus more quickly than they import it. She would like to see experiments testing whether Parc alters the relative rates at which p53 enters and leaves the nucleus. Further work should reveal how this protein shifts p53 to park.

--R. John Davenport

A. Y. Nikolaev, M. Li, N. Puskas, J. Qin, W. Gu, Parc: A cytoplasmic anchor for p53. Cell 112, 29-40 (2003). [Abstract] [Full Text]

January 22, 2003 Citation: R. J. Davenport, Parc'n Brake. Science's SAGE KE (22 January 2003),;2003/3/nw11

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