Lani
01-23-2006, 05:39 PM
Or perhaps at least an early causative step. Amazing the claims put into the last sentence of abstracts! This is the Same post as Rhonda H earlier today--quite a claim! I put off posting it earlier waiting for the original article. Will post that once I get it! Definitely seems an overstretch!
ABSTRACT: Inefficient proteasomal-degradation pathway stabilizes AP-2? and activates HER-2/neu gene in breast cancer [International Journal of Cancer; Subscribe; Sample]
HER-2/neu proto-oncogene is overexpressed in about one fourth of human breast cancers. AP-2 transcription factors bind to the HER-2/neu gene promoter and activate its expression. In a striking concurrence, anomalous abundance of AP-2? protein or its homolog AP-2? is also detected with HER-2/neu protein in mammary tumor-derived cell lines. This suggests that the deregulation of AP-2 is the preceding pathogenic event and probably the pivotal one in this type of mammary carcinogenesis. We examined the process of AP-2? gene expression in mammary carcinoma cell lines to identify where the aberration had occurred. We found no amplification of the AP-2? gene. Its promoter was marginally upregulated; however, it did not significantly increase the mRNA levels. When the AP-2? protein was examined, a remarkable stability was seen in breast cancer cell lines MDA-MB-453 and SK-BR-3, with a half-life of over 30 hr. This is sharply higher than the approximate 1 hr observed in mammary epithelial cell line MCF-10A and murine cell line NIH 3T3. Treatment of MCF-10A and NIH 3T3 cells with the proteasome inhibitor MG-132 showed that AP-2? was ubiquitinated and its level significantly increased. Moreover, this increase was accompanied by elevated levels HER-2/neu protein. In contrast, weaker ubiquitination of AP-2? was seen in MDA-MB-453 and SK-BR-3 cancer cells, and MG-132 treatment did not raise the AP-2? level any further. These results uncover that unusual stability is the main mechanism that raises the levels of AP-2 proteins, and in addition, provide the first clue that defective ubiquitin-dependent proteasomal-degradation pathway is possibly the prime cause that affects the HER-2/neu gene and culminates in breast cancer.
ABSTRACT: Inefficient proteasomal-degradation pathway stabilizes AP-2? and activates HER-2/neu gene in breast cancer [International Journal of Cancer; Subscribe; Sample]
HER-2/neu proto-oncogene is overexpressed in about one fourth of human breast cancers. AP-2 transcription factors bind to the HER-2/neu gene promoter and activate its expression. In a striking concurrence, anomalous abundance of AP-2? protein or its homolog AP-2? is also detected with HER-2/neu protein in mammary tumor-derived cell lines. This suggests that the deregulation of AP-2 is the preceding pathogenic event and probably the pivotal one in this type of mammary carcinogenesis. We examined the process of AP-2? gene expression in mammary carcinoma cell lines to identify where the aberration had occurred. We found no amplification of the AP-2? gene. Its promoter was marginally upregulated; however, it did not significantly increase the mRNA levels. When the AP-2? protein was examined, a remarkable stability was seen in breast cancer cell lines MDA-MB-453 and SK-BR-3, with a half-life of over 30 hr. This is sharply higher than the approximate 1 hr observed in mammary epithelial cell line MCF-10A and murine cell line NIH 3T3. Treatment of MCF-10A and NIH 3T3 cells with the proteasome inhibitor MG-132 showed that AP-2? was ubiquitinated and its level significantly increased. Moreover, this increase was accompanied by elevated levels HER-2/neu protein. In contrast, weaker ubiquitination of AP-2? was seen in MDA-MB-453 and SK-BR-3 cancer cells, and MG-132 treatment did not raise the AP-2? level any further. These results uncover that unusual stability is the main mechanism that raises the levels of AP-2 proteins, and in addition, provide the first clue that defective ubiquitin-dependent proteasomal-degradation pathway is possibly the prime cause that affects the HER-2/neu gene and culminates in breast cancer.