Disease relevance of Sqstm1

• Recently, p62 mutations have been shown to be the cause of the 5q35-linked Paget's disease of bone, a genetic disorder characterized by aberrant osteoclastic activity [1].

High impact information on Sqstm1

• We suggest that p62 may, via LC3, be involved in linking polyubiquitinated protein aggregates to the autophagy machinery [2].
• Reduction of p62 protein levels or interference with p62 function significantly increased cell death that was induced by the expression of mutant huntingtin [2].
• In this study, we report that polymerization of the polyubiquitin-binding protein p62/SQSTM1 yields protein bodies that either reside free in the cytosol and nucleus or occur within autophagosomes and lysosomal structures [2].
• p62 is a highly tyrosyl phosphorylated protein that was first identified in immunoprecipitates of the GTPase-activating protein (GAP) of p21ras from cells transformed by oncogenic nonreceptor tyrosine kinases or stimulated through tyrosine kinase receptors (C. Ellis, M. Moran, F. McCormick, and T. Pawson, Nature 343:377-381, 1991) [3].
• This protein corresponds to the major tyrosine-phosphorylated protein that is induced in differentiating keratinocytes as early as 5 min after calcium addition. p62 phosphorylation was not observed after exposure of these cells to epidermal growth factor, phorbol ester, or transforming growth factor beta [4].

Biological context of Sqstm1

• Sequencing analysis of the 5' flanking region of the STAP gene revealed multiple consensus motifs/sequences for several DNA binding transcription factors [5].
• The STAP gene had a TATA box, but no CCAAT box [5].
• Analysis of the mouse STAP gene isolated from the genomic library revealed that the STAP gene spans a region of over 11 kb and comprises eight exons [5].
• The amino acid sequence homology search also reveals that STAP is identical to a mouse oxidative stress protein, A170, and has 90% homology with a human p62 protein that binds to the tyrosine kinase p56(lck) SH2 domain [5].
• These structural features suggest that the phosphorylation of A170 affects its function and degradation [6].

Anatomical context of Sqstm1

• Northern blot analysis indicated a broad expression profile of STAP mRNA in various tissues and cell lines [5].
• We previously reported cDNA cloning of a novel oxidative stress protein termed A170 from murine macrophages [7].
• Low micromolar levels of hydrogen peroxide and proteasome inhibitors induce the 60-kDa A170 stress protein in murine peritoneal macrophages [7].
• Activation of Nrf2 and accumulation of ubiquitinated A170 by arsenic in osteoblasts [8].
• Hamster oocytes fertilized in vivo in the presence of A-BL2 were all monospermic, suggesting that p62/p56 do not function in blocking polyspermy [9].

Associations of Sqstm1 with chemical compounds

• Furthermore, the level of p62 protein and mRNA was increased in expanded polyglutamine-expressing cells [10].
• The levels of glucose oxidase-induced A170 protein did not decrease after the addition of cycloheximide [7].
• Arsenate also markedly increased ubiquitin-conjugated cellular proteins, suggesting that HMM-A170 was one of the poly-ubiquitinated proteins [8].
• Arsenite (50-100 micro M) also induced accumulation of HMM-A170 and ubiquitin-conjugated proteins [8].
• We demonstrate here that the expression levels of p62 mRNA and protein were increased in Neuro-2a cells and cultured rat hippocampal neurons by different types of proapoptotic treatments, including serum deprivation, okadaic acid, etoposide, and trichostatin A [11].
• When p62 was co-expressed with SOD1 in NSC34 cells, it greatly enhanced the formation of aggregates of the ALS-linked SOD1 mutants, but not wild-type SOD1 [12].

Physical interactions of Sqstm1

• A search of sequence databases revealed that the A170 protein is roughly 90% identical to a human protein that binds to the Src homology 2 domain of the T-cell-specific tyrosine kinase p56lck [13].

Other interactions of Sqstm1

• A specific p62 antibody stained the ubiquitylated polyQ inclusions in expanded polyglutamine-expressing cells, as well as in the brain of the huntingtin exon 1 transgenic mice [10].
• Activation of cellular signaling pathways either by epidermal growth factor, lipopolysaccharide or tumor necrosis factor-alpha did not enhance the level of the A170 protein [7].
• We purified this protein, and, using mass spectrometry, identified it as p62, an ubiquitin-associated domain-containing protein [10].
• ERK 2, CK II, and PKA phosphorylated recombinant A170 as a substrate [6].
• Here we show that p62, like TRAF6, is upregulated during RANK-L-induced osteoclastogenesis and that the genetic inactivation of p62 in mice leads to impaired osteoclastogenesis in vitro and in vivo, as well as inhibition of IKK activation and NF-kappa B nuclear translocation [1].

Analytical, diagnostic and therapeutic context of Sqstm1

• Using cDNA arrays, we observed upregulation of ubiquitin-binding protein p62 expression during serum withdrawal-induced apoptosis in Neuro-2a cells [11].
• To study the subcellular distribution of p62 during the cell cycle of sea urchin embryos, indirect immunofluorescence microscopy was used coupled to a modified detergent extraction procedure [14].

References