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Proteolytic Activation of Protein Kinase C by an ICE/CED 3-like Protease Induces Characteristics of Apoptosis

Tariq Ghayur^*, Margaret Hugunin^*, Robert V. Talanian^*, Sheldon Ratnofsky^*, Christopher Quinlan^*, Yutaka Emoto, Pramod Pandey, Rakesh Datta, Yinyin Huang, Surender Kharbanda, Hamish Allen^*, Robert Kamen^*, Winnie Wong^*, and Donald Kufe

From ^* BASF Bioresearch Corporation, Worcester, Massachusetts 01605; and Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

	Abstract

Top Abstract Materials and Methods Results and Discussion References

 
Recent studies have shown that protein kinase C (PKC) is proteolytically activated at the onset of apoptosis induced by DNA-damaging agents, tumor necrosis factor, and anti-Fas antibody. However, the relationship of PKC cleavage to induction of apoptosis is unknown. The present studies demonstrate that full-length PKC is cleaved at DMQD₃₃₀N to a catalytically active fragment by the cysteine protease CPP32. The results also demonstrate that overexpression of the catalytic kinase fragment in cells is associated with chromatin condensation, nuclear fragmentation, induction of sub-G1 phase DNA and lethality. By contrast, overexpression of full-length PKC or a kinase inactive PKC fragment had no detectable effect. The findings suggest that proteolytic activation of PKC by a CPP32-like protease contributes to phenotypic changes associated with apoptosis.

The protein kinase C (PKC) family consists of multiple subspecies that possess a conserved catalytic domain. The classic or group A isoforms (, β, and ) require Ca²⁺ for activity and contain cysteine-rich motifs that confer phospholipid-dependent binding of diacylglycerol (1). The group A PKCs are cleaved at the third variable region (V₃) by the neutral proteases, calpains I and II, to catalytically active fragments (2). Recent studies have demonstrated that the Ca²⁺-independent isoform, and not the group A PKCs, is selectively cleaved at V₃ to a catalytically active fragment in cells induced to undergo apoptosis (3, 4). Inhibition of apoptosis by overexpression of Bcl-2 or Bcl-x_L is associated with a block of PKC cleavage (3, 4). The finding that PKC is cleaved at a site (DMQD/N) adjacent to aspartic acid has supported the potential involvement of aspartate-specific cysteine proteases which are known to be activated during apoptosis.

The nematode Ced-3 cysteine protease is related to the mammalian interleukin-1β converting enzyme (ICE) (5, 6). The demonstration that overexpression of Ced-3 or ICE induces apoptosis has provided support for involvement of these cysteine proteases in cell death pathways (7). ICE/ Ced-3 family members include Nedd2/Ich-1, CPP32/ YAMA/apopain, Tx/Ich-2/ICE_relII, ICE_relIII, Mch2, Mch3/ ICE-LAP3/CMH-1 (reviewed in reference 8), ICE-LAP6 (9), FLICE/Mch5 (10, 11), and Mch4 (11). ICE cleaves the precursor of IL-1β to the active cytokine (6, 12, 13). Other known substrates of the ICE/Ced-3 family include: (a) poly (ADP-ribose) polymerase (PARP) which is cleaved by CPP32, Mch3 and Ced-3, but not ICE (14–16); and (b) DNA-dependent protein kinase (DNA-PK), the U1 small nuclear ribonucleoprotein and D4-GDP dissociation inhibitor for the Rho family GTPases (D4-GDI), which are cleaved by CPP32 (17, 18). However, the functional role of these cleavage products in the induction of apoptosis is unclear.

The present results demonstrate that PKC is cleaved by CPP32 and not certain other ICE/Ced-3 family members. We also demonstrate that overexpression of the PKC catalytic fragment is involved in the induction of phenotypic changes that are characteristic of apoptosis.

	Materials and Methods

Top Abstract Materials and Methods Results and Discussion References

 
In Vitro Cleavage of PKC and PARP.
The full-length PKC cDNA was cloned into the SpeI and BamH1 sites of a modified pSVβ plasmid (Clontech, Palo Alto, CA). PKC(D327A/D330A) was generated in two steps by overlapping primer extension. PARP cDNA was generated by PCR cloning. The proteins were labeled with [³⁵S]methionine by coupled transcription and translation reactions (Promega, Madison, WI). Labeled proteins were incubated with 5 µg/ml Escherichia coli-derived CPP32β in 50 mM Hepes (pH 7.5), 10% glycerol, 2.5 mM DTT, and 0.25 mM EDTA at room temperature for 30 min. The reaction products were analyzed by electrophoresis in 10-20% SDS–polyacrylamide gels and then autoradiography. For the kinase assays, full-length PKC, PKC(D327A/D330A), PKC catalytic fragment (CF), and PKCCF(K-R) were prepared by coupled transcription and translation. PKC and PKC(D327A/D330A) were incubated with 5 µg/ml CPP32β at room temperature for 30 min. Protein kinase assays using MBP as a substrate were performed as described (PKC Assay Kit; GIBCO BRL, Gaithersburg, MD).

Analysis of Peptide Proteolysis.
Peptides were synthesized and purified to 95% by standard methods and confirmed by mass spectrometry. Reaction mixtures (810 µl) contained: 100 mM Hepes (pH 7.5), 20% (vol/vol) glycerol, 5 µM dithiothreitol, 0.5 mM EDTA, and 380 ng N-His CPP32 (19). Peptide substrates were added to final concentrations of 10 µM. The reaction mixtures were incubated at 30°C. Aliquots were removed at 10 min intervals for 60 min and added to vials containing 3 M HCl to stop the reactions. The amount of substrate remaining at each time was quantitated by reverse phase HPLC. Data were fit to the equation (S_t/S_o) = e^–kt, where k is the decay rate constant equal to V_max/K_m. Observed V_max/K_m values were normalized to 1.00 for the PARP peptide.

Cell Transfections.
Cells were seeded at a density of 1.7 x 10⁵ in each well of 6-well dishes 24 h before transfection. For each well, 2 µg DNA construct and 0.5 µg pSvβ plasmid containing β-gal were coprecipitated with calcium phosphate. Cells were incubated with the coprecipitate for 30 h at 37°C and then analyzed by X-gal staining. Cells (1.7 x 10⁵/well) were also transfected with 2 µg DNA construct for 30 h at 37°C, fixed with 4% paraformaldehyde, postfixed with 5% acetic acid in ethanol and then stained with 5 µg/ml Hoechst dye. For sub-G1 DNA content, cells transfected by lipofectamine were stained with propidium iodide and monitored by FACScan^®. Chromatin condensation was assessed by staining with acridine orange and ethidium bromide (20).

	Results and Discussion

Top Abstract Materials and Methods Results and Discussion References

 
To determine whether PKC is cleaved by one of the known ICE-like proteases, full-length 78-kD PKC labeled with [³⁵S]methionine was incubated with purified recombinant proteases. Cleavage of PKC to a 40-kD fragment was observed with purified CPP32β (14) (Fig. 1 A). In contrast, ICE failed to cleave PKC at concentrations up to 600 U/µl (3). The related Ich-1, Ich-2, Mch2, Mch3, and ICE_relIII proteases also failed to cleave PKC (data not shown). Because PKC is cleaved at DMQD₃₃₀N in vivo (3, 4), we asked whether this site is responsible for CPP32mediated cleavage in vitro. CPP32 may prefer peptidic substrates with aspartic acid at the P1 and P4 positions (15). Consequently, we prepared a PKC mutant with substitution of D327A and D330A. Incubation with CPP32 resulted in no detectable CPP32-mediated cleavage of this mutant to the 40-kD catalytic fragment, while there was partial digestion to a species of 55 kD (not observed with wild-type substrate) (Fig. 1 A). Recombinant CPP32 also cleaved the 116-kD full-length PARP to the predicted 85-kD fragment (14, 15) (Fig. 1 A). Using peptides derived from the cleavage sites of PARP and PKC in proteolytic assays, we found that CPP32 cleaves both substrates and not a peptide spanning the IL-1β maturation site (Table 1). These findings confirm that PKC, like PARP, is a substrate for CPP32.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 1 PKC is proteolytically activated by CPP32 in vitro. (A) PKC (full-length: FL), PKC(D327A/D330A) and PARP were labeled with [35S]methionine and incubated with recombinant CPP32β. The reaction products were analyzed by SDS-PAGE and autoradiography. The kinase active PKC catalytic fragment (CF) and the kinase inactive PKCCF(K-R) were labeled with [35S]methionine and analyzed under similar conditions. (B) Recombinant PKC and PKC (D327A/D330A) were incubated with CPP32 and then assayed for protein kinase activity using MBP as substrate.

 

View this table: [in this window] [in a new window]   Table 1 CPP32 Proteolysis of Peptides Spanning the PARP, PKC, and IL-1β Cleavage Sites

 
We also asked whether cleavage of PKC by CPP32 is associated with activation of the kinase function. Fulllength PKC exhibited a low level of myelin basic protein (MBP) phosphorylation, while incubation with CPP32 resulted in a greater than sixfold increase in kinase activity (Fig. 1 B). In contrast, CPP32 had no detectable effect on kinase function of the PKC(D327A/D330A) mutant (Fig. 1 B). A recombinant 40-kD CF of PKC (amino acids 331676) exhibited constitutive kinase activity, while a mutant of the fragment with K-378 in the ATP binding site mutated to R (K378R; designated K-R) yielded background levels of MBP phosphorylation found with control bacterial lysates (Figs. 1, A and B). These findings collectively demonstrate that CPP32-mediated cleavage of the DMQD₃₃₀N site activates PKC.

To study the role of PKC in apoptosis, we used the transient HeLa cell transfection system previously found to demonstrate induction of apoptosis by ICE-like proteases (7). Cotransfection of the kinase inactive PKCCF(K-R) mutant with the β-galactosidase (β-gal) marker gene had little effect on HeLa cell morphology (Fig. 2 A). Most of the blue X-gal positive cells remained flat and attached to the dish (Fig. 2 A). Cotransfection of the kinase active PKCCF and β-gal resulted in condensed, small blue cells (Fig. 2 B), consistent with the induction of apoptosis (7). Similar findings were obtained with NIH3T3 cells (Figs. 2, C and D). Overexpression of PKC in both cell types also resulted in detachment of non-viable cells into the culture medium.

View larger version (111K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Transfection of the PKC catalytic fragment (CF) induces morphologic changes characteristic of apoptosis. HeLa (upper panels) and NIH3T3 (lower panels) cells were cotransfected with pSvβ-β-gal and vectors expressing: (A and C) kinase inactive PKCCF(K-R) and (B and D) kinase active PKCCF. Transfection was determined by X-gal staining and apoptotic cells were identified by their condensed morphology.

 
Hoechst staining of HeLa cells transfected with a vector that expresses full-length PKC had no detectable changes in nuclear morphology (Fig. 3 A), but overexpression of PKCCF resulted in fragmented nuclei (Fig. 3 B). Transfection of kinase inactive PKCCF(K-R) was associated with a normal nuclear morphology (Fig. 3 C). The changes observed with expression of the PKC CF were also compared to those found upon exposure to 1-β-D-arabinofuranosylcytosine (ara-C), a DNA-damaging agent that induces proteolytic cleavage of PKC and apoptosis (4). Treatment of HeLa cells with ara-C resulted in a similar pattern of nuclear fragmentation (Fig. 3 D).

View larger version (52K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Expression of PKCCF results in nuclear fragmentation. HeLa cells were transfected with vectors that express: (A) full-length PKC; (B) kinase active PKCCF; and (C) kinase inactive PKCCF(K-R). (D) Cells were exposed to 2 µM ara-C. The cells were fixed with paraformaldehyde and then stained with Hoechst dye. Cotransfection of PKCFL, PKCCF and PKCCF(K-R) with pSvβ-β-gal demonstrated transfection efficiencies of 50, 42, and 43%, respectively. Percentage of apoptotic cells for the PKCFL, PKCCF, and PKCCF(K-R) transfected populations was 2, 26, and 4%, respectively. Bar, 15 µM.

 
To confirm that the nuclear changes induced by PKCCF are associated with induction of apoptosis, we assessed the effects of transfection on the appearance of HeLa cells with sub-G1 DNA content. Transfection of the empty vector, full-length PKC or PKCCF(K-R) resulted in 10-15% of cells with sub-G1 DNA (Fig. 4 A and data not shown). By contrast, transfection of PKCCF was associated with 30– 35% of cells with sub-G1 DNA (Fig. 4 A). Cells were also stained with acridine orange and ethidium bromide to assess chromatin condensation (20). Transfection of PKCCF, but not PKCCF(K-R), resulted in the appearance of bright yellow-green nuclear staining of condensed chromatin (Fig. 4 B).

View larger version (46K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Overexpression of PKCCF induces sub-G1 DNA and chromatin condensation. (A) HeLa cells were transfected with PKCFL, PKCCF, or PKCCF(K-R). Cells were assessed for DNA content by flow cytometry at 48 h after transfection. The small triangle denotes G0/G1 DNA. (B) HeLa cells transfected with PKCCF(K-R) (left) and PKCCF (right) were assessed for chromatin condensation after staining with acridine orange and ethidium bromide.

 
To quantify the effects of PKCCF expression on cell viability, we cotransfected PKCCF or PKCCF(K-R) and the green fluorescence gene (Clontech) into HeLa cells. Positive transfectants were selected by flow cytometry, reseeded in culture medium and assayed at 24 h for viability by trypan blue exclusion. Less than 5% of the PKCCF transfectants were viable, while over 90% of the kinase inactive PKCCF(K-R) transfectants were viable and attached to the dish. Viability of 90–95% was observed after transfection of the null vector and sorting. We conclude that the kinase active catalytic domain of PKC induces characteristics typical of cells undergoing apoptosis: (a) size reduction and round morphology; (b) nuclear fragmentation; (c) chromatin condensation; (d) sub-G1 DNA content; and (e) detachment and loss of viability.

Multiple events that lead to destruction of nuclear and cytoplasmic integrity are probably required for apoptosis. Activation of ICE-family proteases may be a central trigger, resulting in the cleavage of substrates such as PARP (21), lamin B1 (22, 23), topoisomerase 1 (23), D4-GDI (18), DNA-PK, and the U1 small nuclear ribonucleoprotein (17). PKC, but not PKC, β, , or , is also cleaved at the onset of apoptosis (3, 4). Little is known about the physiological function of PKC (24, 25). We demonstrate that PKC is cleaved by CPP32 and not other ICE/Ced-3 family members in vitro. The results also demonstrate that expression of the PKC catalytic fragment induces morphologic changes characteristic of apoptosis. We propose that the proteolytic cleavage of PKC is a key mediator of nuclear fragmentation and cell death, and not a bystander effect of protease activation. Moreover, the finding that proteolytic activation of PKC is blocked by Bcl-2 and Bcl-x_L suggests that these anti-apoptotic proteins act upstream to this event (3). Elucidation of the substrates phosphorylated as a consequence of PKC cleavage should provide insights into the pathways activated by the catalytic fragment.

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Top Abstract Materials and Methods Results and Discussion References

 

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