Cancer Genetics

Edited by Steven Benowitz R.A. Steinman, B. Hoffman, A. Iro, C. Guillouf, D.A. Liebermann, M.E. Elhouseini, "Induction of p21 (WAF1/CIP1) during differentiation," Oncogene, 9:3389-96, 1994. (Cited in more than 40 publications as of February 1996) Comments by Richard A. Steinman, University of Pittsburgh Cancer Institute. CELL CYCLIST: Richard Steinman's cell differentiation research may provide clues to cancer development Richard A. Steinman, an assistant professor of medicine at the University of Pittsburgh Cancer Institute, and his collaborators at Temple University in Philadelphia show in this article that a protein, p21(WAF1), plays a key role in triggering cell differentiation. Other scientists previously had found that the p21 protein stalls cell division in the early G1 phase of the cell's cycle in response to DNA damage. The effect was controlled by p53, a well-documented tumor-suppressor gene that was thought to activate p21(WAF1) in damaged cells, giving them time to repair DNA damage before duplicating the DNA. The researchers were trying to understand what might be responsible for keeping undifferentiated cells from continuing through the cell's reproductive cycle. "Like damaged cells, differentiated cells are arrested in the G1 phase of the cell cycle," Steinman notes. "We speculated that the p21(WAF1) gene product might be a candidate for keeping differentiated cells from dividing." Steinman's group believed that if p21(WAF1) played a role in differentiation, then it might be activated by a different pathway from the p53-activation pathway for p21 in damaged cells. The scientists first examined differentiation in blood, liver, and lung cell lines that lacked p53 and discovered that, in fact, "multiple inducers of differentiation" directly turned on p21(WAF1) in these cells. As expected, he says, p21(WAF1) induction correlated with G1 arrest in the differentiating cells. "The work established an association between the p21 (WAF1) cell cycle gene and differentiation, independent of p53, and raised the possibility of alternative mechanisms for achieving cell cycle arrest in settings with high cancer risk involving p53 deficiency," he says. But treating cancers that lack p53 with "alternative p21(WAF1) inducers" may not be so simple, he notes. He and his coworkers also found that an oncogene, or cancer-causing gene, dubbed "myc," "blocked cell differentiation and the ability of the p21(WAF1) gene to cause cell cycle arrest, indicating that oncogenes acting at downstream points can render p21(WAF1) ineffective." Steinman adds that subsequent papers (O. Halevy et al., Science, 267:1018-21, 1995 and S.B. Parker et al., Science, 267:1024-7, 1995) showed that "a control gene for muscle differentiation turned on the p21 gene during differentiation." The researchers currently are identifying a regulatory mechanism for the expression of p21(WAF1) during the various stages of normal blood cell differentiation. "It will let us understand how, in normal development, the exit from the cell cycle and entry into the differentiated state is choreographed, and the molecular mechanisms for doing that," Steinman explains. "It's beginning to be possible to go beyond the descriptive association of cellular functions such as proliferation, differentiation, and apoptosis [programmed cell death], and to establish the molecular controls linking those pathways-namely, linking differentiation with exit from proliferation," he says. "Because that's such an important set of controls, any disruption of those processes can have implications such as cancer. The better the molecular latticework connecting those functions can be defined, the more clearly we can identify early aberrations of that control in cancers or identify targets to correct that disruption."

Cancer Genetics

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