Nature Cell Biology: p21 protein is not always good

In the past 20 years, p21 is considered a "good" protein to indicate good prognosis of tumor therapy, and it is once even seen as a cancer suppressor protein. However, scientists from institutions including University of Athens and University of Manchester have recently revealed its "bad" side. The findings were published in the journal Nature Cell Biology, which has also published some other studies on recombinant proteins like recombinant human proteins.

As a cyclin kinase inhibitor, p21 has always been considered to have close function link with the famous cancer suppressor protein p53. As we all know, p53 is an important cell division checkpoint protein. It ensures the integrity of the genome of a cell by preventing "problem" DNA with defects to spread through replication and cell division until the defects is repaired, thereby curbing the cancer tendency. To do this, p53 would activate many proteins which inhibit cell growth and promote apoptosis, among which is p21 which can make the process of cell division stay in G1 phase. Based on this knowledge, doctors have long been considered the presence of p21 in tumor to be a good sign, thinking that p53 can inhibit tumor growth more effectively in this situation.

However, the researchers found that when p53 is missing, p21 will dramatically promote tumor growth and spread in the body. The authors said, "Without the normal function of p53, the presence of p21 protein would never be a good thing."

Such a conclusion is not envisaged by the original researchers. They initially hoped to find a way to raise the level of p21 protein to achieve the effect of inhibiting tumor. As a result, researchers found another action mechanism of p21.

When p53 is deleted, the continued accumulation p21 protein can inhibit the activity of CRL4Cdt2 E3 ubiquitin ligase, eventually leading the replication process to get out of control. Originally, CRL4Cdt2 E3 ubiquitin ligase should play its role during cell division S phase (i.e., DNA synthesis phase). It prevents multiple copies of DNA in S phase to ensure only one copy by degrading Cdt1, p21 and Set8 and other proteins. If CRL4Cdt2 E3 ubiquitin ligase is inhibited, then the mechanism of DNA replication origin licensing can't work properly, leading to the problem of replication stress and genomic instability. Thus, without "custody" and guidelines of p53, p21 would step toward a carcinogenic "evil way".

Although this finding makes researchers shocked, it also points out another direction - since p21 is dangerous sometimes, then weakening the activity of p21 at that time will be OK. "We now know that is without the control of p53, p21 can lead to uncontrolled cell proliferation, which is a dangerous sign of cancer. Although this discovery breaks our current knowledge, it provides a new through for the development of anticancer therapy,” co-author of this article Professor Paul who is from Townsend University of Manchester said.

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