NEW YORK, September 9, 2004 - Many cancers, including colon, prostate, and leukemia, continue to grow unchecked because they do not respond to a signal to die and stop proliferating from Transforming Growth Factor-beta (TGF-b). The cause of this signaling disruption of the normal cell cycle has not been fully understood. For the first time, scientists at Memorial Sloan-Kettering Cancer Center have discovered the biologic function of the cytoplasmic form of the Promyelocytic Leukemia protein (PML), and identified it as an essential factor in maintaining TGF-b signaling. Their findings, published in the September 9 issue of the journal Nature, explain the link between these two proteins in the development of cancer and suggest that restoring their activity may provide a possible cancer treatment.
"Through our discovery of the biologic function of PML and its essential role in maintaining TGF-b signaling, we can better understand the progression of many human cancers," said Pier Paolo Pandolfi, M.D., Ph.D., Head of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and the study's senior author. "Restoring PML function may correct this signaling defect therefore providing a novel therapeutic target for cancer drugs."
TGF-b is a protein that can suppress tumor development by signaling a cell to stop growing. The unresponsiveness to TGF-b signaling has been associated with a variety of human cancers. In addition to this loss of TGF-b, loss of PML is associated with tumor progression in many human cancers, including prostate, breast, colon, and lung, as shown by Dr. Pandolfi and colleagues in a recently published study in the Journal of the National Cancer Institute. In a later work published in Nature Cell Biology, they also demonstrated an unexpected role for PML in affecting the nucleolar network for tumor suppression and in regulating the function of a gene crucial to the suppression of the genesis of cancer.
In this current work, the Sloan-Kettering researchers found that cytoplasmic PML (cPML) also has a key role in cancer development. It is required for the formation of a signaling complex that is an essential factor in activating TGF-b signaling necessary to suppress the growth of cancer cells. When cPML is lost, TGF-b signaling is disrupted. Primary cells from Pml-null mice are resistant to TGF-b dependent growth arrest, induction of aging (cellular senescence), and cell death (apoptosis). However, when PML function is added back to these cells, this defect is corrected and TGF-induced activity restores normal cell functions.
"The study found an unexpected role of cPML which highlights the importance of analyzing the status of PML in human cancers," said Hui-Kuan Lin, Ph.D., of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering and the study's first author.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
Published on PsychCentral.com. All rights reserved.
Respect ... is appreciation of the separateness of the other person, of the ways in which he or she is unique.
-- Annie Gottlier