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Oncogenes and tumor suppressor genes
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
S. Giordano, S. Corso, P. Conrotto
Tumor cells are different from their normal counterparts in many aspects such as growth control, morphology, cell-cell interactions, membrane properties, cytoskeletal structures and gene expression. In normal cells, growth is strictly controlled. A cell will not proliferate if it does not receive signals from the extracellular environment. These signals are mediated by growth factors, most of which are peptides acting in a paracrine manner. Growth factors interact with specific receptors, located on the plasma membrane, which are transmembrane molecules, endowed with tyrosine kinase activity. Upon ligand binding, receptors undergo dimerization, thus moving into close proximity their intracellular portions. This results in a conformational change of the kinase domain, leading to enzyme activation (Figure 1). The receptor thus autophosphorylates on tyrosine residues that become docking sites for intracellular transducers. Many cytoplasmic proteins contain domains (such as SH2 or PTB) able to recognize the phosphorylated tyrosines (Figure 2). These proteins can be either enzymes (such as phospholipase Oγ, tyrosine phosphatases, cytoplasmic tyrosine kinases, etc.) or adaptors (SHC, Gab1, Gab2, GRB2) or transcription factors (STAT family). Upon interaction with the receptor, these proteins become activated and start to transduce cytoplasmic signals. Eventually, the signal is brought to the nucleus where gene transcription is induced. Each of these steps are negatively regulated by growth inhibitory factors, tyrosine phosphatases, inhibitors of cytoplasmic transducers and nuclear proteins that block progression of the cell cycle (Figures 3 and 4).
Blastic Transformation of Chronic Myelogenous Leukemia: Does BCR-ABL Orchestrate Disease Progression?
Published in Jorge Cortes, Michael Deininger, Chronic Myeloid Leukemia, 2006
Calabretta Bruno, Perrotti Danilo
In contrast, PI-3K and the STAT5 are important pathways required for BCR-ABL transformation and activated in both chronic and blastic phase CML (29,30). BCR-ABL interacts indirectly with the p85 regulatory subunit of PI-3K via various docking proteins, including GRB-2/Gab2 and c-cbl (31). The PI-3K activation via the GRB-2/Gab2 interaction appears pathologically relevant, as Gab2-deficient marrow cells are resistant to BCR-ABL transformation (31). Activation of the PI-3K pathway triggers an Akt-dependent cascade that has a critical role in BCR-ABL transformation and survival of BCR-ABL+ myeloid progenitors (32) by regulation of the subcellular localization and/or activity of several targets, such as BAD, MDM2, IkB-kinase-α, and members of the Forkhead family of transcription factors (33). Consistent with the effects of Akt on many targets, inhibition of the PI-3K/Akt pathway suppresses in vitro colony formation and in vivo leukemogenesis of BCR-ABL-expressing cells (29,32), and marrow cells defective in PI-3K/Akt activation are resistant to BCR-ABL transformation (31). Likewise, several observations suggest the importance of STAT5 in CML. In fact (i) BCR-ABL mutants defective in STAT5 activation were less efficient than the wild-type form in the transformation of 32Dcl3 myeloid precursor cells (34); (ii) a constitutively active STAT5 mutant rescued the leukemogenic potential of STAT5 activation-deficient BCR-ABL mutants (34); and (iii) ectopic expression of a dominant-negative STAT5 mutant suppressed BCR-ABL-dependent transformation of primary mouse marrow cells (34). Furthermore, expression of p210 BCR-ABL in primary murine STAT5A-deficient bone marrow cells, which do not have deficiencies in colony formation, induced a B-ALL or a CML/B-ALL rather than a pure CML chronic phase-like disease in recipient mice (35), suggesting that STA5A is important for BCR-ABL-dependent transformation and development of a CML but not a B-ALL-like disease in mice.
Elevated expressions of SHP2 and GAB2 correlated with VEGF in eutopic and ectopic endometrium of women with ovarian endometriosis
Published in Gynecological Endocrinology, 2020
Yizhou Huang, Tao Zhang, Liqing Chen, Minghua Yu, Qin Liu, Caiyun Zhou, Qile Tang, Linpo Zhou, Hong Zhan, Juanqing Li, Kaihong Xu, Jun Lin
Src-homology-2-domain-containing phosphatase 2 (SHP2), encoded by PTPN11, is a ubiquitously expressed non-receptor protein tyrosine phosphatase (PTP). SHP2 is required for normal development, regulating cell survival, proliferation, migration, and differentiation involved in various signaling pathways downstream of growth factor and cytokine receptors [7]. Activating mutations or dysregulation of SHP2 has been implicated in developmental diseases and multiple cancer types, including leukemia, breast and lung cancer and neuroblastoma [8]. The Grb2-associated binding protein 2 (GAB2) is a scaffolding adapter protein that links plasma membrane receptor signaling with several downstream signal effectors including SHP2 [9]. GAB2 participates in immune response, Alzheimer's disease and human tumorigenesis, particularly in breast cancer, leukemia and ovarian cancer [10–12]. The interaction between GAB2 and SHP2 has been proven to be important in several human malignancies [12–14]. However, the expression pattern and potential role of SHP2 and GAB2 in endometriosis have not been studied.