The VHL tumor suppressor protein | ПРЕЦИЗИОННАЯ ОНКОЛОГИЯ

VHL tumor suppressor protein

Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)

The VHL mRNA is actually translated into two different proteins by virtue of alternative, in-frame, translation initiation codons [11–13]. The long form contains 213 amino acids. The short form is missing the first 53 amino acid residues. In most, but not all, biological assays, the short form and long form behave similarly. Moreover, virtually all of the VHL mutations identified to date affect both the long and the short forms of the protein. Therefore, “pVHL” will be used throughout this chapter when referring to the two protein isoforms generically. pVHL resides primarily in the cytoplasm [14, 15] but shuttles dynamically to and from the nucleus [16, 17]. Some pVHL can also be detected in mitochondria [18] and in association with the endoplasmic reticulum [19]. Restoration of pVHL function in VHL-/clear cell renal carcinomas suppresses their ability to form tumors in vivo but not their ability to proliferate on plastic dishes under standard cell culture conditions [15, 20]. pVHL does, however, inhibit proliferation when cells are grown on specific extracellular matrices, at high confluence, or as threedimensional spheroids [21–25].

VHL-associated neoplasms, including clear cell renal carcinomas, are often highly angiogenic and occasionally cause the excessive production of red blood cells (polycythemia). The former is linked, at least partly, to overproduction of VEGF and the latter to secretion of erythropoietin. These clinical features provided important clues with respect to the biochemical functions of pVHL. In particular, pVHL suppresses the production of hypoxia-inducible mRNAs, including the mRNAs for VEGF and erythropoietin, under normal oxygen conditions [20, 26–29]. Consequently, overproduction of such mRNAs, and the proteins they encode, is a hallmark of pVHL-defective tumors.

__Kidney Cancer_ Principles and Practice-Springer International Publishing (2015) 3.1

Fig. 3.1. Control of HIF activity. Steady-state levels of HIFa are controlled by its rate of synthesis and degradation. The former is regulated by the TORC1 complex, which contains the mTOR kinase. This is especially true for HIF1a. The rate of degradation is under the control of pVHL. When oxygen is present, HIFa becomes prolyl hydroxylated, which marks it for polyubiquitylation by pVHL and subsequent proteasomal degradation. HIFa can dimerize with its partner protein, HIFЯ (also called ARNT), and transcriptionally activate genes such as VEGF and EPO

Mechanistically, pVHL is part of a multiprotein complex that also contains elongin B, elongin C, Cul2, and Rbx1 [30–35]. This complex possesses ubiquitin ligase activity [36–41] and can polyubiquitylate specific substrates, which are then earmarked for destruction by the proteasome. pVHL serves as the substrate recognition component of this ubiquitin ligase complex. The best-documented target of the pVHL ubiquitin ligase is the HIF (hypoxia-inducible factor) transcription factor, which is a heterodimer consisting of an unstable alpha subunit and a stable beta subunit. In the presence of oxygen pVHL binds directly to the HIF alpha subunit and targets it for polyubiquitylation and subsequent proteasomal degradation [28, 38–42] (Fig. 3.1). Under low-oxygen conditions, or in cells lacking functional pVHL, HIFa accumulates and binds to HIFЯ. The HIF heterodimer binds to specific DNA sequences called hypoxia response elements (HREs) in hypoxia-responsive genes such as VEGF and EPO and increases their rate of transcription (Fig. 3.1).

The interaction between pVHL and HIFa requires oxygen because HIFa must be hydroxylated on one (or both) of two conserved prolyl residues in order to be recognized by pVHL [43–47]. Prolyl hydroxylation of HIFa is catalyzed by members of the EglN family [48–50], which are oxygendependent enzymes that serve as cellular oxygen sensors [51]. pVHL contains mutational hotspots called the alpha domain and the beta domain. The alpha domain binds directly to elongin C [30, 52], which recruits the remaining members of the ubitquitin ligase complex, and the beta domain binds directly to hydroxylated HIFa [38, 53, 54].

[contact-form-7 id=»5168″ title=»Контактная форма 1″]