Pepstatins: Aspartic proteinase inhibitors having potential therapeutic applications

Tumminello, Francesca Maria; Bernacki, Ralph J.; Gebbia, Nicola; Leto, Gaetano

doi:10.1002/med.2610130206

Cited by 22 publications

(11 citation statements)

References 41 publications

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“…2c). Pepstatin has been shown to be a potent inhibitor of all members of the aspartic proteinase family (37). The enzymatic activity of this family of proteases is optimum in mostly acidic pH conditions (38), which is consistent with the complete inhibition at pH 7.00 that we observe (Fig.…”

Section: Rop-1 Interacts With Components Of the Daf-2 And Daf-7 Dauersupporting

confidence: 89%

ROP-1, an RNA quality-control pathway component, affectsCaenorhabditis elegansdauer formation

Labbé

Burgess

Rokeach

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Caenorhabditis elegans dauer formation is an alternative larval developmental pathway that the worm can take when environmental conditions become detrimental. Animals can survive several months in this stress-resistant stage and can resume normal development when growth conditions improve. Although the worms integrate a variety of sensory information to commit to dauer formation, it is currently unknown whether they also monitor internal cellular damage. The Ro ribonucleoprotein complex, which was initially described as a human autoantigen, is composed of one major 60-kDa protein, Ro60, that binds to one of four small RNA molecules, designated Y RNAs. Ro60 has been shown to bind mutant 5S rRNA molecules in Xenopus oocytes, suggesting a role for Ro60 in 5S rRNA biogenesis. Analysis of ribosomes from a C. elegans rop-1(؊) strain, which is null for the expression of Ro60, demonstrated that they contain a high percentage of mutant 5S rRNA molecules, thereby strengthening the notion of a link between the rop-1 gene product and 5S rRNA quality control. The Ro particle was recently shown to be involved in the resistance of Deinococcus radiodurans to UV irradiation, suggesting a role for the Ro complex in stress resistance. We have studied the role of rop-1 in dauer formation. We present genetic and biochemical evidence that rop-1 interacts with dauer-formation genes and is involved in the regulation of the worms' entry into the dauer stage. Furthermore, we find that the rop-1 gene product undergoes a proteolytic processing step that is regulated by the dauer formation pathway via an aspartic proteinase. These results suggest that the Ro particle may function in an RNA quality-control checkpoint for dauer formation.Ro ribonucleoprotein complex ͉ aspartic proteinase ͉ ribosome biogenesis ͉ 5S rRNA ͉ daf-2 T he dauer pathway is a specialized stress-resistant, alternative developmental stage of the nematode Caenorhabditis elegans (for review, see ref. 1). Developing worms are prone to form dauer larvae when environmental conditions become unfavorable for growth and reproduction. To make this developmental decision, the worms integrate a variety of sensory information about environmental conditions, including the density of conspecific animals, food availability, and temperature (2, 3). When growth conditions improve, dauer larvae can exit the dauer stage and resume normal development. The subsequent life history parameters of adult animals who passed through the dauer stage, such as brood size and life span, are independent of the time spent as dauer larva. The worm monitors external conditions to determine whether it is favorable to enter the dauer stage rather than to proceed along the normal developmental program, but it is currently not known whether internal conditions, such as previously sustained molecular damage, are also monitored.A complex cascade of genetic interactions regulates entry into the dauer stage, and at least three pathways have been defined: daf-2, daf-7, and daf-11. The daf-2 gene encodes an insulin...

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Section: Rop-1 Interacts With Components Of the Daf-2 And Daf-7 Dauersupporting

confidence: 89%

ROP-1, an RNA quality-control pathway component, affectsCaenorhabditis elegansdauer formation

Labbé

Burgess

Rokeach

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…The supporting role of CD activity in cancer progression, however, cannot be definitively ruled out. Intraperitoneal administration of pepstatin A significantly reduce the number of lung or liver metastases in mice transplanted with Lewis lung carcinoma, MCa mammary carcinoma or M5076 ovarian reticulum cell sarcoma [216][217][218].…”

Section: Mechanism Of Pcd Action On Cancer Cellsmentioning

confidence: 99%

Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

532

474

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For years, it has been held that cathepsin D (CD) is involved in rather nonspecific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans.In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling.Moreover, procathepsin D, secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy.Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell -pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above mentioned processes.In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

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“…Polypeptide inhibitors of this proteinase occur in spare organs of many plants [108] and in tissues of some lower ani- mals [109,110]. Cathepsin D inhibitors have played a substantial role in the studies concerning the structure and mechanism of action of this protease and its tissue location [111][112][113][114][115].…”

Section: Activators and Inhibitorsmentioning

confidence: 99%