Biomedical subjects

R Comolli

Publications and source records attributed to R Comolli.

At least 19 recordsLinked to original sources

PubMed2002

Decrease of TGF-beta1 plasma levels and increase of nitric oxide synthase activity in leukocytes as potential biomarkers of Alzheimer's disease.

A variety of inflammatory proteins have been identified in brains of Alzheimer's disease (AD) patients, including inflammatory cytokines, acute phase proteins and complement components. In the present paper we have investigated the levels of circulating inflammatory mediators as potential biomarkers of this disease, concentrating mostly on transforming growth factor beta (TGF-beta1) in plasma and on nitric oxide synthase (NOS) activity in leukocytes. Plasma and leukocytes were isolated from 48 sporadic AD and 23 healthy control subjects of same age and sex. Since alpha2-Macroglobulin (alpha2M), an acute phase protein possibly involved in AD, is an important modulator of TGF-beta1 activity, binding and targeting this cytokine to its appropriate site of action, we have investigated the possible complex between TGF-beta1 and alpha2M in plasma of the same subjects. The results demonstrate a significant reduction of TGF-beta1 levels in plasma of AD patients. A complex between alpha2M and TGF-beta1 occurred in AD as well as healthy elderly control subjects, however, with no significant differences. Moreover, alpha2M appeared to bind only the inactive form of this cytokine. In contrast, NOS activity increased significantly in leukocytes of AD patients. Therefore, we suggest the combined determination of TGF-beta1 in the plasma and of NOS activity in the leukocytes as biomarkers of AD.

Alzheimer Disease↗

PubMed2002

Higher levels of melanin and inhibition of cdk2 activity in primary human melanoma cells WM115 overexpressing nPKCdelta.

Many studies have attempted to define the state of differentiation of melanoma cells and to correlate it with other critical parameters of malignancy such as the tumorigenic and metastatic nature of the cells. In the present paper we focused on the possible relationships between the novel protein kinase C isoform nPKCdelta, melanin synthesis and proliferative capacity in a primary human melanoma cell line WM115. Cells were transfected to produce overexpression of this isoform and the effects on melanin synthesis, cyclin-E dependent kinase (cdk2) activity and cyclin E expression were studied. It was shown that translocation of nPKCdelta into the nucleus affects melanin synthesis and inhibits cdk2 activity. As a compensatory effect, the level of cyclin E increases. In view of these results we suggest a model for the role of nPKCdelta in melanoma cells that may offer a new therapeutic perspective.

Active Transport, Cell Nucleus↗

PubMed2000

Different levels of TGFbeta, IL-10, IFNgamma and gelatinase A occur in experimental white and black metastases induced by bryostatin 1 or by phorbol ester-treated BL6T murine melanoma cells.

Bryostatin 1 and phorbol esters reduce the intracellular melanin level in high metastatic overexpressing nPKCdelta BL6 (BL6T) cells, thereby inducing white experimental metastasis in syngeneic mice. We evaluate here the possible differences between white and black metastases induced by both treatments on the proliferative and metastatic potential as well as on the expression of some cytokines involved in the metastatic process such as TGFbeta, IL-10 and IFNgamma. The level of expression of gelatinase A is also considered. White and black metastases induced after the injection of bryostatin 1- or phorbol ester-treated cells into the tail vein of syngenic mice were isolated and analysed for the levels of LDH usually used as markers of cytotoxicity, for the levels of cytokines and gelatinase A or dissociated and cultured in vitro for a few passages. The cultured cells were analysed in vitro for the proliferative capacity and the melanin synthesis. The same cells were also re-injected into syngeneic mice and the number of experimental metastases were counted after 17 days or injected with matrigel in order to quantify the proliferative capacity in vivo. The results show only one significant difference between bryostatin I and phorbol ester, namely the cells obtained from white bryostatin 1-treated cells return to a black phenotype after a few passages in culture. This suggests that PKC mediates many of the biological effects of bryostatin 1 but that its effect is lost in vitro. On the other hand, white and black metastases (at least for metastases induced by BL6T cells treated with phorbol ester) do appear significantly different. In vivo white metastases show lower levels of LDH, lower levels of proliferative capacity into matrigel, higher levels of TGFbeta and IFNgamma and, when re-injected into syngeneic mice, give big black metastases. Therefore, in murine melanoma cells, the treatment with bryostatin I induces the appearance of a white population expressing different levels of TGFbeta, IFNgamma, IL-10 and gelatinase A. Such a white population is more difficult to diagnose and is capable of turning into a more aggressive phenotype under suitable environmental conditions.

Animals↗

PubMed2000

Overexpression of nPKCdelta in BL6 murine melanoma cells enhances TGFbeta1 release into the plasma of metastasized animals.

Transforming growth factor-beta (TGFbeta) contributes to the promotion of invasion, metastasis, angiogenesis and even immunosuppression. Since overexpression of the delta isoform of protein kinase C (nPKCdelta) in BL6 murine melanoma cells (BL6T cells) increases their metastatic capacity, we investigated the possible involvement of TGFbeta1 in this process. Immunohistochemical analysis demonstrated lower levels of TGFbeta1 in BL6T lung metastases compared with BL6 lung metastases. On the other hand, higher levels of this cytokine, in particular in its active form, occur in the plasma of BL6T metastasized animals, suggesting a nPKCdelta-dependent TGFbeta1 release. Therefore, nPKCdelta-dependent TGFbeta1 release and activation may be involved in the greater angiogenic and metastatic capacity of murine melanoma BL6T cells.

Animals↗

PubMed2000

Overexpression of novel protein kinase C delta in BL6 murine melanoma cells inhibits the proliferative capacity in vitro but enhances the metastatic potential in vivo.

In this study we analysed the effect of overexpressing novel protein kinase C delta isoform (n-PKC delta) on melanin synthesis and metastatic potential in the highly metastatic BL6 murine melanoma cells. The proliferative capacity in vitro and into matrigel in vivo were also examined. Although murine melanocytes express the n-PKC delta isoform, BL6 cells do not express this isoform at levels detectable by Western blot analysis. In untransfected and transfected cells we also studied the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA), a modulator of specific isoforms of PKC, and of bryostatin 1, a potent immunomodulator and antineoplastic drug and a partial agonist of PKC. Our results demonstrate a pivotal role for this isoform in melanin synthesis and the close relationship between n-PKC delta expression and its association with the particulate fraction, melanogenesis and metastatic potential. In fact, heterogeneous BL6 cells overexpressing n-PKC delta and all the clones isolated showed increased intracellular melanin and metastatic capacity. TPA and bryostatin 1 decreased n-PKC delta expression, the intracellular melanin level and metastatic capacity in both cell lines. Therefore both treatments were able to abolish the effects of overexpressing n-PKC delta.

Adjuvants, Immunologic↗

PubMed1999

Age-dependent modulation of PKC isoforms and NOS activity and expression in rat cortex, striatum, and hippocampus.

Recently, PKC has been shown to play a pivotal role in physiological brain functions, connected with the memorizing processes and their correspondent progressive decline with brain aging. We have studied the age-dependent changes of PKC isoforms activity in connection with NOS expression and activity in specific brain areas such as hippocampus, cortex and striatum. Starting from middle aged rats, a significant inactivation of c-PKC isoforms occurred, with respect to young animals, in all the brain areas analysed. However, in middle aged animals, no significant changes in the protein level of the main PKC isoforms expressed in brain were demonstrated. Moreover, in the hippocampus and in the cortex of middle aged rats, an increased level of NOS activity--a substrate of PKC whose phosphorylation by the kinase inhibits NOS activity--has been demonstrated, reaching the same level that occurs in striatum. However, only in the hippocampus, deeply implicated in learning and memory functions, an increase of nuclear c-PKC activity and of i- and n-NOS mRNA levels was shown. Taken together, these results indicate that down-regulation of c-PKC activity occurring in middle aged rats, leads to higher levels of NO that may contribute to cell damage and to alter the neuronal physiological functions as described in older animals. Moreover, in the hippocampus, our results suggest a relationship between the translocation of c-PKC to the nucleus and the enhancement of the expression of i- and n-NOS.

Aging↗

PubMed1998

Opposite effects of TPA on G1/S transition and on cell size in the low metastatic B16F1 with respect to high metastatic BL6 murine melanoma cells.

Phorbol esters, known activators of c- and n-protein kinase C (PKC) isoforms, play a pivotal role in tumor promotion. In order to better understand the relationships between PKC activation, the metastatic potential and the proliferative capacity, we have analyzed the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment on the proliferative as well as on the cell cycle distribution and on the cell size of low and high metastatic murine B16F1 and B16-BL6 (BL6) melanoma cells, respectively. TPA-treated B16F1 cells showed an increased proliferative capacity up to 72 h, the cytofluorimetric analysis revealing an increased number of cells in the S + G2-M phase of the cell cycle. In contrast, TPA-treated BL6 cells reached a plateau at 48 h and showed an increased cell volume in the G1 and S phases of the cell cycle, with a reduction in the percentage of cells in the S + G2-M phase. Taken together, our results indicate opposite effects of TPA treatment in murine melanoma cells of different metastatic potential. TPA could cause a block in the G1 phase of the cell cycle with enhanced cell volume in high metastatic BL6 cells. The same treatment, on the contrary, induced an increased entry into the cell cycle of low metastatic B16F1 cells, suggesting a relationship between cell proliferation and the metastatic potential of B16 murine melanoma cells. Moreover, under the present conditions, classical PKC isoforms were inactivated, suggesting the involvement of the TPA-dependent novel PKCs.

Animals↗

PubMed1998

c-PKC-dependent modulation of plasma fibrinogen levels during the acute-phase response in young and old rats.

The expression and subcellular distribution of liver cPKC alpha and beta, nPKC delta and aPKC zeta isoenzymes and the plasma levels of fibrinogen were measured in young, 2- and 6-month-old, and aged, 24-month-old, normal and turpentine-treated rats, to induce an aseptic inflammatory condition and the acute-phase response. In young and old rats a down-regulated expression of cPKC alpha and, to a lesser extent, beta isoenzymes, was observed 8 h after turpentine administration, i.e. at times preceding the maximal expression of fibrinogen mRNA. Under these conditions, the plasma fibrinogen levels peaked by 24 h in young animals, being up to 7-fold over the values of untreated controls at 72 h. By contrast, old untreated control rats showed 4-fold increases of basal plasma fibrinogen levels compared with young controls, with down-regulated expression of cPKC alpha. In old rats, treatment with turpentine increased up to 1.9-fold over the basal control values the fibrinogen concentration within 72 h. Levels similar to those of young turpentine-treated animals were reached at this time. The results of this study suggest a prominent role for cPKC alpha in eliciting the synthesis of fibrinogen after inducing an acute-phase response with turpentine administration in young as well as old rats. This isoform may act by regulating the serine phosphorylation of Stat3 transcription factor, whose activation is under IL-6 control, a multifunctional cytokine that is proving to be a major contributor to the acute-phase response. No evidence for a role of aPKC zeta or of nPKC delta was demonstrated under these conditions.

Acute-Phase Reaction↗

PubMed1998

Angiogenic capacity and lung-colonizing potential in vivo is increased in weakly metastatic B16F1 cells and decreased in highly metastatic BL6 cells by phorbol esters.

The development of tumor metastasis is a multistep process. Key aspects of this process are the interaction of tumor cells with the extracellular matrix, digestion of, and motility through the basement membrane and the induction of angiogenesis. In this study, we analysed the effects of a low dose of TPA (12-tetradecanoylphorbol-13-acetate; 0.1 microM on angiogenesis, proteolytic activity and lung colonizing potential of both weakly metastatic B16F1 cells and highly metastatic BL6 murine melanoma cells. Our results demonstrated opposite effects of TPA in the two cell lines. TPA-treated B16F1 cells showed enhanced release of basic FGF (bFGF) and vascular endothelial growth factor (VEGF) and increased angiogenic capacity and lung colony formation in vivo. In contrast, TPA-treated BL6 cells demonstrated a dramatic reduction of angiogenic and gelatinolytic activity and metastatic capacity. However, both cell lines showed an induction of VEGF as well as bFGF expression by TPA treatment suggesting that in BL6 cells antagonistic factors, inhibiting the angiogenic and metastatic capacity, are induced by this treatment.

Animals↗

PubMed1998

Inhibition of protein kinase C-alpha isoform enhances the P-glycoprotein expression and the survival of LoVo human colon adenocarcinoma cells to doxorubicin exposure.

The aim of the present paper was to analyse the effect of long-term inhibitory treatment, for at least 7 days, of individual protein kinase C (PKC) isoforms on the survival of LoVo human colon adenocarcinoma cells to doxorubicin exposure. The treatment for 2 h, after plating the cells, and after 3 days with 1 microM Gö6976, a specific inhibitor of protein kinase C (PKC)-alpha and -betal isoforms, induced on day 7 in LoVo cell lines (WT) a significant increased survival when these cells were exposed to increasing doxorubicin concentrations. In contrast, resistant LoVo cells (DX) did not show significant changes in the survival to doxorubicin exposure when incubated with the inhibitor of the same specific PKC isoforms. In addition, Gö6976 reduced the PKC-alpha activity (the main calcium-dependent PKC isoforms expressed) in both cell lines with contemporary increased expression. Under such conditions, an increased nuclear activity and an increased P-glycoprotein expression occurred only in WT-treated cells with respect to untreated cells. Taken together, our data indicate a specific relationship between PKC-alpha inhibition, the increased nuclear PKC-alpha activity as well as the increased expression of P-glycoprotein, possibly causing the acquisition of a resistant phenotype in WT LoVo cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Activation of protein kinase C-alpha isoform in murine melanoma cells with high metastatic potential.

Metastasis is a multistep process in which protein kinase C (PKC) appears to be significantly involved. We analysed the activity and expression of classical (alpha, beta, gamma) and novel PKC epsilon isoforms in B16-F1 and B16-BL6 melanoma cells maintained under different culture conditions in vitro. We used high and low concentrations of tyrosine and phenylalanine in different media (DMEM or RPMI 1640 respectively) that affect the metastatic potential and also the proliferative capacity of the cells. We also tested a weakly metastatic amelanotic B78-H1 melanoma cell line which is unaffected by the different culture conditions. In both B16 melanoma cell lines activation of PKC alpha (without increased expression) occurred under growth conditions permissive of metastasis (DMEM). In contrast, the weakly metastatic amelanotic B78-H1 cell line showed a substantial inactivation of this isoform in the two different culture media, suggesting a specific involvement of PKC alpha in the metastatic process. Moreover, in B16 melanoma cells, novel PKC epsilon was activated under culture conditions which stimulated growth but not metastasis (RPMI 1640). In order to define the relationship between PKC activation and the metastatic process we also determined the release of cathepsin B. No correlation between PKC activity and cathepsin B release in either B16 melanoma cell lines could be demonstrated.

Animals↗

PubMed1997

Changes in protein kinase C alpha, delta and in nuclear beta isoform expression in tumour and lung metastatic nodules induced by diethylnitrosamine in the rat.

PKC, a family of 11 related isoforms, appears deeply implicated in carcinogenesis and in the metastatic process, however, little being known on the specific role of each isoform in that process. In this work we analysed the subcellular distribution and the in situ expression of classical PKC (alpha and beta) isoforms and the expression of PKC delta in the tumour and lung-metastases induced in the rat using the 'resistant hepatocyte' model of diethylnitrosamine-induced hepatocarcinogenesis. With respect to control untreated liver, an activation and increased expression of PKC alpha was observed in tumour and lung metastatic nodules, while cytosolic and membrane PKC beta was undetectable. In contrast, nuclear PKC beta showed an increased activity in the tumour and a marked increased activity and expression in metastatic nodules, suggesting a possible role of such isoform in the metastatic process. The analysis of PKC delta expression revealed a down regulation in both tissues with respect to control untreated liver, suggesting the inhibitory role of such isoform on tumour cell proliferation in agreement with our previous observations. Taken together, these results point to a different role for PKC alpha and delta in the development of tumour and metastatic nodules using the 'resistant hepatocyte' model of liver carcinogenesis, and suggest a possible involvement of nuclear PKC beta in the development of secondary tumours.

Animals↗

PubMed1995

Membrane and cytosolic protein phosphorylation patterns in the early stages of DEN-induced hepatocarcinogenesis in rats fed a high or low protein diet.

The membrane and cytosolic protein phosphorylation patterns in the early stages of diethylnitrosamine-induced rat liver carcinogenesis, promoted by 2-acetylaminofluorene in the diet plus partial hepatectomy (DEN-AAF-PH), were analyzed by two-dimensional gel electrophoresis in animals fed a low protein (5% casein) diet, or the original high protein (24% casein) diet, in order to modulate the development of GST-P-positive preneoplastic lesions. Compared with untreated controls, membrane and cytosolic protein phosphorylation patterns changed only slightly in low protein-fed rats 7 days post-hepatectomy, with no appearance of enzyme-altered hyperplastic foci in the liver sections. By contrast, high protein-fed animals demonstrated GST-P-positive preneoplastic lesions 7 days post-hepatectomy and several acidic and more basic high M(r) phosphorylated membrane (between 97 and 116 kDa) as well as cytosolic (between 97 and 200 kDa) proteins could be detected. In the presence of enzyme-altered hepatocytes in the liver sections, low protein-fed rats demonstrated at 60 days post-hepatectomy cytosolic protein phosphorylation patterns remarkably similar to those shown by 24% casein-fed animals at 7 days post-hepatectomy, suggesting close correlation between protein phosphorylation patterns and development of preneoplastic lesions during the early stages of DEN-AAF-PH liver carcinogenesis. This may arise by a constitutive activation of one or more signal transduction pathways, possibly involving protein kinase C, during liver tumour promotion.

Animals↗

PubMed1995

Alanine transport in rat liver plasma membrane vesicles during the acute-phase response in young and old rats.

The Na(+)-dependent transport of L-alanine into liver plasma membrane vesicles isolated from young, 2-month-old, and aged, 24-month-old, normal and turpentine-treated rats, to induce an aseptic inflammatory condition and the acute-phase response, was studied. In old rats, alanine transport maintained the same features observed in young controls, being strictly Na(+)-and electrical potential-dependent. However, old rats showed a twofold increase in the Vmax value for alanine uptake compared with young controls, the affinity constant (Km) remaining unmodified. Four hours after turpentine treatment, the Vmax value of alanine transport in young rats was 2.5-fold over that observed in untreated controls. In contrast, old turpentine-treated rats demonstrated only slight increases in this value, compared to untreated old controls. In both young and old turpentine-treated rats, the Km values of alanine transport remained almost unmodified. Since dysregulation of interleukin 6 (IL-6) gene expression, a multifunctional cytokine that is proving to be a major contributor to the acute phase response, occurs with advancing age in different animal species, the increased alanine transport across liver plasma membrane vesicles observed in old "normal" rats might be related to an increased IL-6 production, inducing an acute phase protein synthetic activity, in these animals.

Acute-Phase Reaction↗

PubMed1995

Preclinical evaluation of the ribosome-inactivating proteins PAP-1, PAP-S and RTA in mice.

In a preclinical mouse model the plant ribosome-inactivating proteins (RIPs) pokeweed antiviral proteins PAP-1, and PAP-S and ricin A-chain (RTA) induced a pathological elevation of serum concentrations of glutamate pyruvate transaminase (GPT) and blood urea nitrogen (BUN) and had a significant immunosuppressive effect on B- and T-lymphocytes. The present analysis and comparison of the biodistribution and systemic/organ toxicity associated with RIP injection suggest a possible in vivo mechanism of action of PAP-1 and PAP-S and identify several limitations in the clinical use of these two toxins and RTA. When administered intravenously, PAP-1 and PAP-S consistently accumulated in kidneys and induced histologically documented damage to kidney and liver, with a LD50 of 3.3 mg/kg and 1.6 mg/kg for PAP-1 and PAP-S, respectively. In mice injected with PAP-S after chlorpromazine (CPZ) administration, GPT levels returned to normal between 24 and 72 h after toxin injection, while the BUN levels remained elevated. Mortality of the animals was delayed but all mice eventually succumbed. All the three toxins inhibited the expansion of anti-sheep red blood cells (SRBC) antibody-forming cells and the production of anti-SRBC antibody levels, although PAP-S showed the most potent activity. Despite the immunosuppressive activity, all toxins were highly immunogenic.

Alanine Transaminase↗

PubMed1995

Over-expression of protein kinase C delta is associated with a delay in preneoplastic lesion development in diethylnitrosamine-induced rat hepatocarcinogenesis.

The purpose of this study was to determine if decreasing dietary protein from 24% (high protein) to 5% casein (low protein), substituting sucrose and cornstarch isocalorifically for casein, would modify the activity of protein kinase C (PKC) alpha and beta isoenzymes, as well as the expression of PKC alpha, beta, delta and zeta subtypes in the particulate, soluble and nuclear fractions of rat liver, and the development of gamma-glutamyltranspeptidase (GGT)-positive foci and nodules in the early stages (4, 7 and 60 days post-hepatectomy) of diethylnitrosamine-induced carcinogenesis promoted by 2-acetylaminofluorene in the diet plus partial hepatectomy (DEN-AAF-PH). In rats fed the 5% casein diet, body and liver weights decreased significantly compared with 24% casein-fed animals. However, the PKC total activity was unmodified. In 5% casein-fed rats, over-expression of PKC delta in the liver particulate fraction was detected at 7 and 60 days post-hepatectomy, with no significant PKC alpha and beta isoform activation. These animals showed only scattered GGT-positive hepatocytes at 60 days post-hepatectomy, with no appearance of hyperplastic foci or preneoplastic nodules. In contrast, rats fed the 24% casein diet demonstrated a progressive loss of PKC delta expression in the particulate fraction during tumour promotion, with activation and increased membrane association of PKC alpha and beta subtypes. These animals developed hyperplastic cell foci and preneoplastic nodules at 7 and 60 days respectively. Taken together, the results of this study suggest that overexpression of PKC delta in the liver particulate fraction of low protein-fed rats may play a specific role in inhibiting the development of hepatocellular focal lesions in the early stages of DEN-AAF-PH-induced carcinogenesis and confirm the role for nuclear PKC beta in promoting the selective growth of carcinogen-initiated hepatocytes in high protein-fed animals. No evidence for a role of PKC zeta in the carcinogenic process could be demonstrated.

2-Acetylaminofluorene↗

PubMed1994

Membrane and nuclear protein kinase C activation in the early stages of diethylnitrosamine-induced rat hepatocarcinogenesis.

The activity and expression of Ca(2+)-dependent cPKC alpha and beta isoenzymes in the particulate, soluble (cytosolic) and nuclear fractions of rat liver and the expression of Ca(2+)-independent nPKC delta and aPKC zeta were examined during the early stages (30 and 60 min, 24 and 96 h and 7 and 60 days post-hepatectomy) of the Solt-Farber 'resistant hepatocyte' model of diethylnitrosamine (DENA)-induced hepatocarcinogenesis in Fischer 344 rats and related to the presence of gamma-glutamyl transpeptidase (GGT)-positive hyperplastic cell foci and persistent nodules in rat liver. Total PKC activity was unmodified by the carcinogenic treatment. In contrast, the PKC activity in the particulate, as well as nuclear fractions increased with time, reaching a maximum 60 days post-hepatectomy, with a decrease in the cytosolic activity. In carcinogen-treated animals maximal expression of cPKC alpha and beta isoenzymes was present 7 days post-hepatectomy, while no changes in nPKC delta and aPKC zeta immunoreactivity were detected. In the nucleus, no cPKC alpha isoform expression was observed, the cPKC beta expression being maximal at 60 days. Seven and 60 days post-hepatectomy GGT-positive hyperplastic cell foci and persistent nodules were present in rat liver respectively. Taken together, the results of this study suggest a role for nuclear cPKC beta and for cPKC alpha in promoting the selective growth of carcinogen-initiated hepatocytes in rat liver. No evidence for a role of Ca(2+)-independent nPKC delta and aPKC zeta isoenzymes in the early stages of DENA-induced liver carcinogenesis could be demonstrated.

Animals↗

PubMed1993

Biochemical and immunological characterization of calcium-dependent and -independent PKC isoenzymes in renal ischemia.

The PKC alpha, beta, delta, epsilon and zeta isoenzyme changes in the rat kidney cortex have been investigated after temporary occlusion of the renal artery, followed by reperfusion for up to 4 h. Increased PKC alpha, delta and epsilon immunoreactivity and PKC alpha activity occurred within 60 min of postischemic reflow, while PKC beta and zeta were unmodified. Increased PKC beta activity was present at later times of reflow (120 min), suggesting that the initial events of the regenerative repair response after an ischemic insult implicate the activation of specific PKC isoenzymes (alpha, delta, epsilon), playing a role in the control of cell proliferation.

Animals↗