Inhibition of Human Type IV Collagenase by a Highly Conserved Peptide Sequence Derived from Its Prosegment

Stetler-Stevenson, William G.; Talano, Julie-An; Gallagher, Mary Ellen; Krutzsch, Henry C.; Liotta, Lance A.

doi:10.1097/00000441-199109000-00009

Cited by 39 publications

(12 citation statements)

References 41 publications

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“…Removal of Va177 by C-terminal truncation let to complete loss of inhibitory activity, as did substitution of Cys 75. The conserved sequence, MRKPRCGNPDV, has been shown to inhibit active human Type IV collagenase [4]. Our data confirm and extend this observation and those of Park et al [8], who showed that PRCGVPDV was a weak inhibitor of transin, the rat equivalent of human stromelysin, The data are consistent with the hypothesis that these peptides inhibit stromelysin via coordination of Cys 75 with the active-site zinc.…”

Section: Discussionsupporting

confidence: 92%

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Peptides based on the conserved prodomain sequence of matrix metalloproteinases inhibit human stromelysin and collagenase

Hanglow¹,

Lugo²,

Walsky³

et al. 1993

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Prostromelysin, a member of the family of matrix metalloproteinases, is secreted as a zymogen which is activated after cleavage of the His81-Phe82 bond. The 82 amino acid propeptide that is removed during activation contains 12 amino acids, MRKPRC75GVPDVG, that are highly conserved in all MMPs. We evaluated a series of peptides that span this region for their ability to inhibit stromelysin. The hexapeptide, Ac-RCGVPD, and the pentapeptide, Ac-RCGVP had IC50 values of approx. 10 microM. The tetrapeptide, Ac-RCGV, was somewhat less potent with an IC50 of 60 microM. Smaller peptides, e.g. Ac-RCG, were significantly less potent as inhibitors. Substitutions of Cys75 with Ser resulted in a complete loss of inhibitory activity. The peptides in this series also inhibited human fibroblast collagenase.

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Section: Discussionsupporting

confidence: 92%

“…76/1001, 340 Kingsland Street, Nutley, NJ 07110, USA Cys 75 is thought to coordinate with the active-site zinc [3] and to maintain the proenzyme in an inactive form. Since peptide sequences from the propeptide domain inhibit MMPs [4], the goal of this study was to define the minimal sequence in [Met69-GlyS~ able to inhibit stromelysin.…”

Section: Introductionmentioning

confidence: 99%

Peptides based on the conserved prodomain sequence of matrix metalloproteinases inhibit human stromelysin and collagenase

Hanglow¹,

Lugo²,

Walsky³

et al. 1993

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“…In vitro studies of the activation mechanism of this enzyme has yielded new insights into the molecular basis of proenzyme latency (Stetler-Stevenson et al, 1991). In this study, AAC-11 transfected cancer cells expressed an elevated level of MMP-2 protein as assessed by immunoblotting.…”

Section: Kim Et Almentioning

confidence: 96%

AAC-11 Overexpression Induces Invasion and Protects Cervical Cancer Cells from Apoptosis

Kim

Cho

Kim

et al. 2000

Laboratory Investigation

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SUMMARY:To identify the genes involved in cervical carcinogenesis, we applied the mRNA differential display (DD) method to analyze normal cervical tissue, cervical cancer, metastatic lymph node, and cervical cancer cell line. We cloned a 491-bp cDNA fragment, CC231, which was present in metastatic tissue and cervical cancer cell line, but absent in normal cervical and cervical cancer tissues. The 491 bp cDNA fragment has 98% homology to the previously published sequence, AAC-11 (antiapoptosis clone 11). The levels of AAC-11 mRNA expressions in nine normal cervical and nine primary cervical cancer tissues were low. Its expression was higher in three metastatic tissues and five cervical cancer cell lines (HeLa, CaSki, SiHa, CUMC-3, and CUMC-6). Invasion of matrigel and adhesion to laminin by AAC-11 transfected CUMC-6 cells were increased by approximately 2-fold and 4-fold, respectively. Northern blot analysis showed that matrix metalloproteinase (MMP)-2 and membrane type 1 MMP (MT1-MMP) genes were found to be expressed in high levels in AAC-11-transfected cancer cells. But MMP-2 and MT1-MMP were not expressed in cells transfected with vector alone or wild-type cells. AAC-11-transfected cells expressed an elevated level of MMP-2 protein as assessed by immunoblotting. On the contrary, tissue inhibitor of MMP (TIMP-2) expression was detectable in cells transfected with vector alone or wild-type cells, respectively. Its expression was undetectable in AAC-11 transfected cells. In cervical cancer cells transfected with AAC-11, the expression of ␤-catenin was up-regulated. These suggest that overexpressions of MMP-2 and MT1-MMP, loss of TIMP-2 expression, and up-regulation of ␤-catenin by AAC-11 transfection may contribute to the development of cervical cancer invasion. AAC-11 gene transfection increased cervical cancer cell colonization. The effect of AAC-11 on cultured cervical cancer cells was associated with antiapoptotic process. Approximately 50% of the AAC-11 transfected cells in serum-free medium died after 2 weeks, compared to 1 week for vector alone or wild-type cells. These results suggest that AAC-11 may serve as a candidate metastasis-related and apoptosis-inhibiting gene in human cervical cancer. (Lab Invest 2000, 80:587-594).

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“…The amino terminal portion of the zymogen contains a highly conserved sequence with a free cysteine residue adjacent to the activation locus which is lost following conversion of the latent proenzyme forms. Synthetic peptides containing the conserved consequence KPRCGV(X)PD, corresponding to the prosegment portion of MMPs, are capable of inhibiting activated MMP-2 [26]. We reported a similar prosegment peptide corresponding to rat MMP-3 (transin), LMHKPRCGVPDVGG (splMP), inhibits both MMP-2 and MMP-3 from several species [17].…”

Section: Invasive Potentialmentioning

confidence: 99%

Differences in proliferation and invasion by normal, transformed and NF1 Schwann cell cultures are influenced by matrix metalloproteinase expression

Muir

1995

Clin Exp Metast

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Loss of negative growth regulation and high invasive potential are neoplastic traits often associated with abnormal expression of matrix metalloproteinases (MMPs). We previously found MMP-3 (stromelysin/transin) was secreted by quiescent rat Schwann cell cultures and expressed potent antiproliferative activity. In the present study we observed that human Schwann cells and cutaneous neurofibroma Schwann cell cultures secreted abundant MMP-3 and their proliferation was inhibited by autologous and rat Schwann cell conditioned media. Antiproliferative activities were depleted by immunoadsorption with anti-stromelysin antibodies. In contrast, plexiform neurofibroma cultures did not secrete MMP-3 and failed to respond to Schwann cell antiproliferative activities associated with MMP-3. Quiescent Schwann cells constitutively secreted low levels of MMP-2 (gelatinase A) and showed a low invasion potential in filter-based assays of basement membrane invasion. Cyclic AMP elevation, which profoundly influences cell differentiation, increased the invasion potential of rat Schwann cells and caused a corresponding increase in secretion of MMP-2. Schwann cells immortalized by protracted elevation of cAMP, as well as a schwannoma cell line (D6P2T), also rapidly invaded a reconstituted basement membrane and over-expressed MMP-2. Similarly, neurofibroma Schwann cells were highly invasive and secreted up to 10-fold more MMP-2 than normal human Schwann cells. Additionally, only cutaneous neurofibroma Schwann cell cultures secreted MMP-9 (gelatinase B) and MMP-1 (interstitial collagenase) and also invaded native type I collagen barriers. Cultures of normal Schwann cells and plexiform neurofibroma tumor expressed little or no MMP-1 and did not invade type I collagen barriers. These results suggest a role for MMPs in the control of proliferation and invasion by Schwann cells and in the formation of peripheral nerve sheath tumors.

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Inhibition of Human Type IV Collagenase by a Highly Conserved Peptide Sequence Derived from Its Prosegment

Cited by 39 publications

References 41 publications

Peptides based on the conserved prodomain sequence of matrix metalloproteinases inhibit human stromelysin and collagenase

Peptides based on the conserved prodomain sequence of matrix metalloproteinases inhibit human stromelysin and collagenase

AAC-11 Overexpression Induces Invasion and Protects Cervical Cancer Cells from Apoptosis

Differences in proliferation and invasion by normal, transformed and NF1 Schwann cell cultures are influenced by matrix metalloproteinase expression

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