A new tumor-specific variant of GRP78 as target for antibody-based therapy

Rauschert, Nicole; Brändlein, Stephanie; Holzinger, Elisabeth; Hensel, Frank; Müller-Hermelink, H. K.; Vollmers, H. Peter

doi:10.1038/labinvest.2008.2

Cited by 120 publications

(108 citation statements)

References 51 publications

(82 reference statements)

Supporting

Mentioning

104

Contrasting

Order By: Relevance

“…The asterisks indicate the smaller 72 kDa band detected by BiP antibody. This band was previously proposed to be a degradation product of wild type BiP (95). WT lenses also express two BiP bands upon longer exposure (not shown).…”

Section: Perk Pathway Is Activated In the Transgenic Lenses-supporting

confidence: 55%

Abnormal Expression of Collagen IV in Lens Activates Unfolded Protein Response Resulting in Cataract

Firtina

Danysh

Bai

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Human diseases caused by mutations in extracellular matrix genes are often associated with an increased risk of cataract and lens capsular rupture. However, the underlying mechanisms of cataract pathogenesis in these conditions are still unknown. Using two different mouse models, we show that the accumulation of collagen chains in the secretory pathway activates the stress signaling pathway termed unfolded protein response (UPR). Transgenic mice expressing ectopic Col4a3 and Col4a4 genes in the lens exhibited activation of IRE1, ATF6, and PERK associated with expansion of the endoplasmic reticulum and attenuation of general protein translation. The expression of the transgenes had adverse effects on lens fiber cell differentiation and eventually induced cell death in a group of transgenic fiber cells. In Col4a1 ؉/⌬ex40 mutant mice, the accumulation of mutant chains also caused low levels of UPR activation. However, cell death was not induced in mutant lenses, suggesting that low levels of UPR activation are not proapoptotic. Collectively, the results provide in vivo evidence for a role of UPR in cataract formation in response to accumulation of terminally unfolded proteins in the endoplasmic reticulum.The ocular lens is a transparent, cellular structure that refracts light onto the retina, resulting in high resolution vision. Many environmental risk factors and single gene defects are known or hypothesized to result in clouding of the lens, a condition known as cataract. Cataract is the primary cause of blindness worldwide (1, 2), with autosomal dominant congenital cataract being the leading cause of treatable childhood blindness (3, 4). Cataract surgery is the most commonly performed surgical operation in the United States and consumes 60% of the Medicare budget for vision (5, 6).Cataract can be a multifactorial disease and is often associated with systemic or genetic disorders, such as diabetes and Lowe syndrome (7-9). Notably, human diseases caused by mutations in extracellular matrix (ECM) 4 genes are also often associated with an increased risk of cataract. Stickler and Marshall syndromes are two disorders caused by mutations in the COL2A1 gene that are associated with the early onset of distinctive cataracts (10, 11). Alport syndrome, caused by mutations in either the COL4A3, COL4A4, or COL4A5 genes, is also associated with lens capsule abnormalities and cataract formation (12)(13)(14). Humans carrying mutations in the COL4A1 locus often exhibit lens abnormalities and cataracts along with porencephaly and sporadic intracerebral hemorrhage (15-19). To date, approximately 13 independent mutations in the mouse Col4a1 locus and three independent mutations in mouse Col4a2 locus have been found to cause vacuolar cataract and lens abnormalities in mice (19 -21). However, the underlying mechanisms of cataract pathogenesis resulting from these collagen mutations are still unknown.In other tissues, mutations in genes encoding secretory pathway proteins have been found to cause endoplasmic reticulum (ER) stress and...

show abstract

Section: Perk Pathway Is Activated In the Transgenic Lenses-supporting

confidence: 55%

Abnormal Expression of Collagen IV in Lens Activates Unfolded Protein Response Resulting in Cataract

Firtina

Danysh

Bai

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…[17][18][19] Cell surface GRP78 is also a major autoantigen in various cancers. [20][21][22] As opposed to its ERbased role in apoptosis and inhibition of protein synthesis, as a cell surface receptor, GRP78 signaling results in a net increase in DNA synthesis, protein synthesis and cellular proliferation. [23][24][25] Studies suggest that central to its function in this regard is the cell surface interaction between GRP78 and MTJ1, a DnaJ-like protein.…”

mentioning

confidence: 99%

Patterns of GRP78 and MTJ1 expression in primary cutaneous malignant melanoma

et al. 2010

View full text Add to dashboard Cite

Cell surface expression of glucose-regulated protein 78 (GRP78) occurs in several types of cancer; however, its role in the behavior of primary cutaneous melanoma is not well studied. The association of cell surface GRP78 with other proteins such as MTJ1 stimulates cell proliferation. In this study, we characterized the pattern of expression of GRP78 and MTJ1 in invasive primary cutaneous melanomas and analyzed the relationships between the pattern of expression and various clinicopathological parameters. We found two patterns of GRP78 expression in invasive primary cutaneous melanoma. One pattern showed a gradual fading of protein expression from superficial to deeper levels within the same tumor. The second pattern of expression showed a similar fading with an abrupt regaining of expression at the deep invasive edge of the melanoma. These two distinct patterns of GRP78 expression correlated with both patient survival and depth of tumor invasion. A moderate MTJ1 expression was found to be associated with decreased patient survival; however, no significant associations were observed between patterns of GRP78 and MTJ1 expression. Our study (1) describes two distinct patterns of GRP78 in invasive primary cutaneous melanoma, (2) inversely correlates regain of GRP78 expression with patient survival, and (3) suggests a modifying effect of MTJ1 on GRP78 in enhancing tumor aggressiveness.

show abstract

“…15,16 Using a proteomics approach, SAM-6 was found to specifically bind to a previously unreported 82 kDa glycosylated form of GRP78. 17 Together, these studies suggest that targeting GRP78 may be a viable approach to kill tumor cells.…”

mentioning

confidence: 98%

“…mediated death. 13,17 How then would GRP78 ligation lead to cell death? Use of the SAM-6 antibody resulted in a marked non-physiologic accumulation of intracellular lipids prior to apoptosis induction.…”

mentioning

confidence: 99%

“…As mentioned above, an 82 kDa glycosylated GRP78 in addition to the unglycosylated protein can be found in cancer cells at the cell surface. 17 It is probable that any C-terminal GRP78 antibody used to elicit cell death would likely also bind to the glycosylated form. Future studies are needed to confirm GRP78 glycosylation and to identify amino acids on which this modification is found to address its relevance and significance in tumor targeting.…”

mentioning

confidence: 99%

See 1 more Smart Citation