High-mobility group protein HMG-I/HMG-Y is a protein that in humans is encoded by the HMGA1gene.
This gene encodes a non-histone chromatin protein involved in many cellular processes, including regulation of inducible gene transcription, DNA replication, heterochromatin organization, integration of retroviruses into chromosomes, and the metastatic progression of cancer cells.
HMGA1 proteins are quite small (~10-12 kDa) and basic molecules and consist of three AT-hooks with the RGRP (Arg-Gly-Arg-Pro) core motif, a novel cross-linking domain located between the second and third AT-hook and a C-terminal acidic tail characteristic for the HMG family comprising HMGA, HMGB and HMGN proteins.
HMGA1-GFP fusion proteins are highly dynamic in vivo (determined using FRAP analysis), but in contrast also show nanomolar affinity to AT-rich DNA in vitro (determined biochemically) which might be explained due to the extensive post-transcriptional modifications in vivo. HMGA1 preferentially binds to the minor groove of AT-rich regions in double-stranded DNA using its AT-hooks. It has little secondary structure in solution but assumes distinct conformations when bound to substrates such as DNA or other proteins. HMGA1 proteins have high amounts of diverse post-tranlational modifications and are located mainly in the nucleus, especially in heterochromatin, but also in mitochondria and the cytoplasm.
Recently it has been shown that HMGA1 proteins, HMGA1a and HMGA1b, can cross-link DNA fibers in vitro and can induce chromatin clustering in vivo suggesting a structural role of HMGA1 proteins in heterochromatin organization. At least seven transcript variants encoding two different isoforms (HMGA1a, HMGA1b) have been found for this gene. The splice variant HMGA1c with only two AT hooks and no acidic tail is in discussion to be a real member of the HMGA family.
Mice lacking their variant of HMGA1, i.e., Hmga1-/- mice, are diabetic, show a cardiac hypertrophy and express low levels of the insulin receptor.
Role in progression of prostate cancer and suppression by microRNA
On Tuesday, May 13, 2014, an online news story article was featured on the University of Cincinnati's home page, linking to UC Health healthNEWS, which detailed a study by two Cincinnati Cancer Center researchers (the Center is a partnership between the University, UC Health, and Cincinnati Children's Hospital Medical Center), featured in the Friday, May 16, 2014 edition of the journal PLOS ONE. It stated,: "... findings by Cincinnati Cancer Center researchers, showing that a tumor suppressive microRNA, when activated by an anti-estrogen drug, could contribute to development of future targeted therapies, are important." ... ""MicroRNAs, or miRNAs, are short RNA molecules that play a prominent role in regulating gene expression. One miRNA can target multiple genes, but their expression is often hijacked by cancer cells and disrupts multiple cancer-causing or tumor-suppressing pathways,” says Shuk-Mei Ho, PhD, director of the CCC and Jacob G. Schmidlapp Chair of Environmental Health and professor at the University of Cincinnati (UC) College of Medicine. She along with Ricky Y.K. Leung, PhD, member of the CCC, assistant research professor in the department of environmental health and member of the UC Cancer Institute, and their team identified a new miRNA, known as hsa-miR-765, which is specifically activated by a Food and Drug Administration (FDA)-approved anti-estrogen drug (fulvestrant). "This miRNA suppresses expression of HMGA1, a gene that was shown in previous studies to be associated with prostate cancer progression and recurrence,” says Leung. "These findings do not only contribute to new insights on the effects of anti-estrogen but also the potential of using miRNA for monitoring drug efficacy and for future RNA-based therapy developments." "This study also highlights the potential use of this anti-estrogen or miRNA in patients with recurrent prostate cancer, for whom there is no treatment, and raises the possibility of using anti-estrogen or miRNA treatments in preventing or slowing progression for primary prostate cancer.” Using cultured prostate cancer specimens from patients who were given a single 250 mg dose of fulvestrant, researchers found that hsa-miR-765 acted as a tumor suppressor when its expression was increased by the use of fulvestrant. "Both the anti-estrogen and the hsa-miR-765 mimic suppressed HMGA1 protein expression,” Ho says. "Levels of hsa-miR-765 were increased, and HMGA1 expression was almost completely lost in prostate cancer specimens from patients treated with a single dose of fulvestrant 28 days before removal of their prostate glands. "These findings reveal a unique fulvestrant signaling process involving the increased regulation of hsa-miR-765 that suppresses the HMGA1 protein as part of the mechanism underlying the tumor suppressor action in prostate cancer. This could lead to newer treatment options with less toxicity for these patients.” The research was conducted with the University of Pittsburgh, and had monetary support from a VA Merit Award, the National Institutes of Health (NIH), the Hong Kong University Grant Council-General Research Fund, Chinese University of Hong Kong Direct Research Grants, and the Investigator-sponsored Study Program of AstraZeneca; the researchers cited no conflict of interest.
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