Test USA su anticancro italiano
Riconoscimento americano per la ricerca oncologica 'made in Italy'. L'agenzia regolatoria d'Oltreoceano Food and Drug Administration (Fda) ha dato il via libera ai test clinici su un nuovo farmaco antitumorale nato nei laboratori del Nerviano Medical Sciences (Nms), alle porte di Milano. La molecola blocca una proteina oncogena chiamata Cdc7, responsabile della proliferazione incontrollata delle cellule tumorali, spiega in una nota il Nms, già partner di multinazionali farmaceutiche come Pfizer, Bristol-Myers Squibb e Genentech, nonché di aziende biotecnologiche e numerosi centri universitari. La Fda - si legge nel comunicato - ha completato positivamente l'esame della domanda di Nms per testare, per la prima volta nell'uomo, il farmaco anti-Cdc7. I dati preclinici sul composto, pubblicati recentemente su 'Nature Chemical Biology', dimostrano infatti che l'inibizione della proteina oncogena Cdc7 induce la morte delle cellule tumorali e blocca la crescita di diversi tipi di cancro negli animali da esperimento. Il 'semaforo verde' della Fda apre quindi la strada alla sperimentazione di una terapia innovativa in studi di fase I su pazienti oncologici. La notizia "è anzitutto un riconoscimento della qualità e della capacità di innovazione della ricerca italiana in campo oncologico - commenta Francesco Colotta, direttore Ricerca e Sviluppo di Nms - La scoperta di questo nuovo farmaco è stato frutto esclusivamente del lavoro dei nostri ricercatori del Centro ricerche di Nerviano - tiene a puntualizzare l'esperto - e grazie alla loro competenza e passione saremo i primi al mondo a esplorare questo nuovo meccanismo antitumorale", conclude.
1. FUNCTION: Seems to phosphorylate critical substrates that regulate the G1/S phase transition and/or DNA replication. Can phosphorylates MCM2 and MCM3.
- The mRNA levels of these genes underwent cell cycle-dependent oscillations with a peak at G1/S phase; they may be regulated by E2F motifs
2. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
3. SUBUNIT: Forms a complex with either DBF4/DBF4A or DBF4B, leading to the activation of the kinase activity.
4. INTERACTION: P11802:CDK4; NbExp=1; IntAct=EBI-374980, EBI-295644; P38936:CDKN1A; NbExp=1; IntAct=EBI-374980, EBI-375077; P42771:CDKN2A; NbExp=1; IntAct=EBI-374980, EBI-375053; Q7L590:MCM10; NbExp=1; IntAct=EBI-374980, EBI-374912; P25205:MCM3; NbExp=1; IntAct=EBI-374980, EBI-355153; O43913:ORC5L; NbExp=1; IntAct=EBI-374980, EBI-374928; Q9Y5N6:ORC6L; NbExp=1; IntAct=EBI-374980, EBI-374840;
5. SUBCELLULAR LOCATION: Nucleus.
6. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=1; Comment=A number of isoforms may be produced; Name=1; IsoId=O00311-1; Sequence=Displayed;
7. SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CDC7 subfamily.
8. SIMILARITY: Contains 1 protein kinase domain.
9. WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/cdc7/";
Role of Polyamines
Identification of stimulators and inhibitors of Cdc7 kinase in vitro. 2008
Kakusho N, Taniyama C, Masai H.
Cdc7 is a serine-threonine kinase that regulates initiation and progression of DNA replication. The activity of purified Cdc7 kinase is significantly stimulated by polyamines such as spermine or spermidine. Positively charged polymers of lysine or arginine also stimulate its kinase activity, whereas the negatively charged substances such as polyglutamate or nucleic acids significantly inhibit the kinase activity. Spermine affects both the K(m) and V(max) of Cdc7 kinase for a minichromosome maintenance (MCM) substrate. We also found that histones, lysine- and arginine-rich basic proteins, can stimulate Cdc7 kinase activity, and a MCM complex in association with histone is a more efficient substrate of Cdc7 than the free MCM complex. These results identify potential cellular inhibitors and stimulators of Cdc7 kinase and suggest that Cdc7 may be another target of cellular polyamines and that histones may stimulate Cdc7-mediated phosphorylation of chromatin-bound substrates. Ectopic expression of an antizyme, known to reduce the cellular polyamine levels, resulted in reduction of Cdc7-mediated phosphorylation of MCM4 protein, suggesting physiological roles of polyamines in regulation of Cdc7 kinase activity in the cells.
Polyamine synthesis inhibition induces S phase cell cycle arrest in vascular smooth muscle cells. 2009
Spermidine or spermine is essential for the aerobic growth of Saccharomyces cerevisiae. 1991
Balasundaram D, Tabor CW, Tabor H.
Laboratory of Biochemical Pharmacology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
A null mutation in the SPE2 gene of Saccharomyces cerevisiae, encoding S-adenosylmethionine decarboxylase, results in cells with no detectable S-adenosylmethionine decarboxylase, spermidine, and spermine. This mutant has an absolute requirement for spermidine or spermine for growth; this requirement is not satisfied by putrescine. Polyamine-depleted cells show a number of microscopic abnormalities that are similar to those reported for several cell division cycle (cdc) and actin mutants. These include a striking increase in cell size, a marked decrease in budding, accumulation of vesicle-like bodies, absence of specific localization of chitin-like material, and abnormal distribution of actin-like material. The absolute requirement for polyamines for growth and the microscopic abnormalities are not seen if the cultures are grown under anaerobic conditions.
