Features of the Proteasome Pool in Spontaneously Occurring Malignant Tumors of the Mammary Gland in Mice
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ANISMS OF NORMAL AND PATHOLOGICAL TISSUE DEVELOPMENT
Features of the Proteasome Pool in Spontaneously Occurring Malignant Tumors of the Mammary Gland in Mice T. M. Astakhovaa, E. V. Moiseevab, and N. P. Sharovaa, * a
Koltsov Institute of Developmental Biology of Russian Academy of Sciences, Moscow, 119334 Russia Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997 Russia *e-mail: [email protected]
bShemyakin-Ovchinnikov
Received April 19, 2020; revised April 28, 2020; accepted April 30, 2020
Abstract—The aim of this work is to investigate the features of the proteasome pool in malignant tumors of mammary glands on a unique model of inbred BLRB/BYRB mice characterized by a high probability of spontaneous development of this type of cancer. It was found that the proteasome pool of mammary glands was relatively stable and it did not change in mice of various physiological states: normal females of different age and a tumor carrier. However, with the formation of malignant tumors, this stability is violated, and the proteasome pool undergoes complex changes. In general, it increases in the number of proteolytic subparticles. At the same time, its chymotrypsin-like activity increases disproportionately more intensively, which indicates additional mechanisms for its regulation. These mechanisms include the detected increased expression of activators PA28αβ and 19S RC as well as changes in the subunit composition of proteasomes due to increased expression of the immune subunits LMP2 and LMP7. The amount of each of the studied components in the proteasome pool increased in the tumor in different ways. The most significant increase was observed in the amount of two components, 19S RC activator and LMP2 subunit, which indicates the prospects of their use as targets for breast cancer therapy. However, we must not forget that these components are also important for the vital functions of normal cells. Therefore, when creating new drugs, we should simultaneously develop methods for their targeted delivery to the tumor or other ways of safe use. Keywords: immune proteasomes, proteasome regulators, proteasome activity, mammary cancer, BLRB/BYRB mouse model DOI: 10.1134/S1062360420050021
INTRODUCTION Identifying the molecular mechanisms of the appearance and growth of malignant tumors of various etiologies is one of the most urgent tasks of modern developmental biology. In this regard, it seems promising to study proteasomes, the ubiquitous multisubunit proteases that carry out the most important metabolic pathway and are theoretically capable of cleaving any cellular protein (Kondakova et al., 2020). Mammalian cells have the most numerous set of multiple forms of proteasomes, which differ in the structure and methods of recognition and hydrolysis of certain protein substrates. A special place in the pool of mammalian proteasomes belongs to immune proteasomes containing proteolytic subunits of LMP2 (β1i), LMP10 (MECL1, β2i), and LMP7 (β5i), respectively, instead of subunits β1, β2, and β5 constitutive p
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