The growth and metastasis of prostate tumors arising from loss of the lipid and protein phosphatase PTEN is initially restrained by transforming growth factor–β (TGF-β) signaling, which activates the transcription factor SMAD4 to increase the expression of various genes, including those encoding the cell cycle regulators cyclin D1 and p21. Qin et al. investigated the mechanisms by which slowly growing, nonmetastatic (indolent) PTEN-null prostate tumors overcome the negative feedback provided by TGF-β signaling and become malignant. A greater proportion of human prostate tumors showed increased staining for the transcription factor COUP-TFII in the nucleus compared with normal prostate epithelial cells. Furthermore, increased abundance of COUP-TFII predicted the risk of recurrence in individuals with prostate cancer. Prostate tumor progression in mice with a prostate-specific deletion of Pten was delayed by a concomitant prostate-specific deletion of COUP-TFII and was enhanced by prostate-specific overexpression of COUP-TFII. Individuals with prostate cancer could be stratified into low- and high-risk groups for recurrence according to the abundance of transcripts for PTEN, SMAD4, p21, cyclin D1, and a COUP-TFII gene signature obtained from prostate cancer PC3 cells. In PC3 cells, knockdown of COUP-TFII increased TGF-β–induced gene transcription and the activity of a reporter gene for SMAD4. COUP-TFII coimmunoprecipitated with SMAD4 from human tumor samples, and the binding of SMAD4 to the promoters of the genes encoding p21 and cyclin D1 was decreased by COUP-TFII overexpression in mice with a prostate-specific deletion of Pten. These results suggested that COUP-TFII prevented the binding of SMAD4 to the promoters of its target genes. Thus, COUP-TFII neutralizes TGF-β signaling in PTEN-null prostate tumors to enable growth and metastasis.
https://stke.sciencemag.org/content/6/258/ec13
From Indolent to Metastatic
From Indolent to Metastatic
Debbie
Re: From Indolent to Metastatic
“SMAD4 gene
SMAD family member 4”
https://ghr.nlm.nih.gov/gene/SMAD4
Protein-coding gene in the species Homo sapiens”
https://en.m.wikipedia.org/wiki/Cyclin_D1
“Is p21 an oncogene?”
https://mct.aacrjournals.org/content/5/6/1385
“The Role of the Cyclin-dependent Kinase Inhibitor p21 in Apoptosis 1 Supported in part by NIH Grant R01 DK56283 (to A. L. T.) for the p21 research and Campus Research Board and Illinois Department of Public Health Penny Severns Breast and Cervical Cancer grants (to A. L. G.).1”
Abstract
Cancer develops when the balance between cell proliferation and cell death is disrupted, and the ensuing aberrant proliferation leads to tumor growth. The cyclin-dependent kinase inhibitor p21 is induced by both p53-dependent and -independent mechanisms following stress, and induction of p21 may cause cell cycle arrest. As a proliferation inhibitor, p21 is poised to play an important role in preventing tumor development. This notion is supported by data indicating that p21-null mice are more prone to spontaneous and induced tumorigenesis, and p21 synergizes with other tumor suppressors to protect against tumor progression in mice. However, a number of recent studies have pointed out that in addition to being an inhibitor of cell proliferation, p21 acts as an inhibitor of apoptosis in a number of systems, and this may counteract its tumor-suppressive functions as a growth inhibitor. In the current review, we discuss the role of p21 in regulating cell death and the potential relevance of its expression in cancer.
https://mct.aacrjournals.org/content/1/ ... f_ipsecsha
SMAD family member 4”
https://ghr.nlm.nih.gov/gene/SMAD4
“Cyclin D1“The SMAD4 protein serves both as a transcription factor and as a tumor suppressor. Transcription factors help control the activity of particular genes, and tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled way.”
Protein-coding gene in the species Homo sapiens”
https://en.m.wikipedia.org/wiki/Cyclin_D1
“Is p21 an oncogene?”
https://mct.aacrjournals.org/content/5/6/1385
“The Role of the Cyclin-dependent Kinase Inhibitor p21 in Apoptosis 1 Supported in part by NIH Grant R01 DK56283 (to A. L. T.) for the p21 research and Campus Research Board and Illinois Department of Public Health Penny Severns Breast and Cervical Cancer grants (to A. L. G.).1”
Abstract
Cancer develops when the balance between cell proliferation and cell death is disrupted, and the ensuing aberrant proliferation leads to tumor growth. The cyclin-dependent kinase inhibitor p21 is induced by both p53-dependent and -independent mechanisms following stress, and induction of p21 may cause cell cycle arrest. As a proliferation inhibitor, p21 is poised to play an important role in preventing tumor development. This notion is supported by data indicating that p21-null mice are more prone to spontaneous and induced tumorigenesis, and p21 synergizes with other tumor suppressors to protect against tumor progression in mice. However, a number of recent studies have pointed out that in addition to being an inhibitor of cell proliferation, p21 acts as an inhibitor of apoptosis in a number of systems, and this may counteract its tumor-suppressive functions as a growth inhibitor. In the current review, we discuss the role of p21 in regulating cell death and the potential relevance of its expression in cancer.
https://mct.aacrjournals.org/content/1/ ... f_ipsecsha
Debbie