The c- erb A gene belongs to a multigene family that encodes transcriptional regulatory proteins including the v- erb A oncogene product, steroid hormone receptors, and the vitamin D3 receptor. A v- erb A DNA probe encoding the DNA-binding region of the v- erb A protein was used to screen a human complementary DNA testis library. One of the clones isolated, erb A-T-1, was found to encode a 490-amino acid protein ( erb A-T). The erb A-T polypeptide shows high homology with the proteins encoded by both the chicken c- erb A and the human c- erb A-β genes but is most closely related to the chicken gene. The chicken c- erb A and the human c- erb A-β genes encode high-affinity receptors for thyroid hormone, and here it is shown that the erb A-T protein binds specifically to 3,5,3 ′-triiodo-L-thyronine with a dissociation constant of 3.8 ± 0.2 × 10 ^-10 M . These data imply that more than one thyroid hormone receptor exists in humans and that these receptors might have different tissue- and gene-activating specificities.

Chandra V, et al. J Gynecol Oncol. 2015 Nov;27(1):e8. https://doi.org/10.3802/jgo.2016.27.e8

Autophagy is a highly regulated catabolic process involving lysosomal degradation of intracellular components, damaged organelles, misfolded proteins, and toxic aggregates, reducing oxidative stress and protecting cells from damage. The process is also induced in response to various conditions, including nutrient deprivation, metabolic stress, hypoxia, anticancer therapeutics, and radiation therapy to adapt cellular conditions for survival. Autophagy can function as a tumor suppressor mechanism in normal cells and dysregulation of this process (ie, monoallelic Beclin-1 deletion) may lead to malignant transformation and carcinogenesis. In tumors, autophagy is thought to promote tumor growth and progression by helping cells to adapt and survive in metabolically-challenged and harsh tumor microenvironments (ie, hypoxia and acidity). Recent in vitro and in vivo studies in preclinical models suggested that modulation of autophagy can be used as a therapeutic modality to enhance the efficacy of conventional therapies, including chemo and radiation therapy. Currently, more than 30 clinical trials are investigating the effects of autophagy inhibition in combination with cytotoxic chemotherapies and targeted agents in various cancers. In this review, we will discuss the role, molecular mechanism, and regulation of autophagy, while targeting this process as a novel therapeutic modality, in various cancers.

Flex-Het drugs induce apoptosis in multiple types of cancer cells, with little effect on normal cells. This apoptosis occurs through the intrinsic mitochondrial pathway accompanied by generation of reactive oxygen species (ROS). The objective of this study was to determine if direct or indirect targeting of mitochondria is responsible for the differential sensitivities of cancer and normal cells to Flex-Hets. Mitochondrial effects and apoptosis were measured using JC-1 and Annexin V-FITC dyes with flow cytometry. Bcl-2, Bcl-x_L, and Bax were measured by Western blot. Flex-Hets induced mitochondrial swelling and apoptosis in ovarian cancer cell lines but had minimal to no effects in a variety of normal cell cultures, including human ovarian surface epithelium. Effects on inner mitochondrial membrane (IMM) potential were variable and did not occur in normal cells. Two different antioxidants, administered at concentrations shown to quench intracellular and mitochondrial ROS, did not alter Flex-Het–induced mitochondrial swelling, loss of IMM potential, or apoptosis. Inhibition of protein synthesis with cycloheximide also did not prevent Flex-Het mitochondrial or apoptosis effects. Bcl-2 and Bcl-x_L levels were decreased in an ovarian cancer cell line but increased in a normal culture, whereas Bax expression was unaffected by Flex-Hets treatment. In conclusion, ROS seems to be a consequence rather than a cause of mitochondrial swelling. The differential induction of apoptosis in cancer versus normal cells by Flex-Hets involves direct targeting of mitochondria associated with alterations in the balance of Bcl-2 proteins. This mechanism does not require IMM potential, ROS generation, or protein synthesis. [Mol Cancer Ther 2007;6(6):1814–22]