Scientists clarify role of phosphatase and tensin homolog tumor suppressor gene

Apr 23 2006

Jiwang Zhang, Ph.D., formerly a Senior Research Associate at the Stowers Institute for Medical Research, and Linheng Li, Ph.D., Associate Investigator, are credited as the first and last authors, respectively, on a paper highlighting several previously unknown functions of phosphatase and tensin homolog (PTEN), an important tumor suppressor gene.

The findings, published on the Nature Website on April 23, identified an intrinsic pathway involving PTEN that helps control the transitions that stem cells make between the quiescent and active states. The results demonstrate the importance of the intermediate 'activated' state that describes stem cells that are between the extremes of quiescence and rapid cycling. PTEN functions to decide whether to progress further though the cell cycle or return to a quiescent (G0) state. Disrupting PTEN in stem cells results in more active cycling and a loss of the quiescent pool of stems cells that is necessary for long-term stem cell maintenance.

PTEN can be phosphorylated in response to other signals that modulate its function. The Li Lab's work demonstrated distinct populations of hematopoetic stem cells (HSCs) with phosphorylated and unphosphorylated forms of PTEN, suggesting that PTEN phosphorylation may be a 'sensor' that could help integrate external cues with the HSC quiescence/activation switch.

"Although the primary mutation occurs in stem cells, leading to short-term expansion of normal stem cells, this mutation alone is not enough to support unlimited expansion of either normal or cancer stem cells," said Dr. Li. "A secondary mutation is therefore required to empower the leukemia cells resulting from this mutation to undergo unlimited expansion. Exploring the nature of the secondary mutation, together with the primary mutation in PTEN, can help to understand the self-renewal ability of stem cells and perhaps will identify new molecules that can be targeted to provide effective leukemia treatment without adversely affecting normal stem cells."

"Stem cells hold great promise for the treatment of many human diseases," said Robb Krumlauf, Ph.D., Scientific Director. "But the body's limited supply of adult stem cells and our current inability to expand stem cells outside of the body have created major bottlenecks in developing practical therapies. These findings, paired with Dr. Li's earlier work, are bringing us closer to translating this research into long-awaited therapies."

Additional contributing authors from the Stowers Institute include Justin Grindley, Ph.D., Senior Research Associate; Tong Yin, Ph.D., Postdoctoral Research Associate; Sachintha Jayasinghe, Laboratory Manager I; Cici He, Research Specialist II; Jason Ross, Predoctoral Researcher; Jeffrey Haug, Managing Director - Cytometry Facility; Dawn Rupp, Research Technician II; Kimberly Porter-Westpfahl, Research Technician I; Leanne Wiedemann, Ph.D., Staff Scientist. Hong Wu, Ph.D. at University of California at Los Angeles also contributed to the article.

"This publication was a true cooperative effort, which would not have been possible without the contributions of Drs. Grindley, He, and Yin, and the members of the Cytometry core facility," said Dr. Li. "No single person can take credit for these findings, so we're very fortunate to have such a dedicated team of collaborators here at the Stowers Institute."