CIP/KIP and INK4 families of Cyclin-dependent kinase inhibitors (CKIs) are well-established cell cycle regulatory proteins whose canonical function is binding to Cyclin-CDK complexes and altering their function. Initial experiments showed that these proteins negatively regulate cell cycle progression and thus are tumor suppressors in the context of molecular oncology. However, expanded research into the functions of these proteins showed that most of them have non-canonical functions, both cell cycle-dependent and independent, and can even act as tumor enhancers depending on their posttranslational modifications, subcellular localization, and cell state context. This review aims to provide an overview of canonical as well as non-canonical functions of CIP/KIP and INK4 families of CKIs, discuss the potential avenues to promote their tumor suppressor functions instead of tumor enhancing ones, and how they could be utilized to design improved treatment regimens for cancer patients.

• Klíčová slova
• CIP/KIP, Cancer, Cyclin-dependent kinase inhibitors, INK4, Oncogenic signaling, Posttranslational modification, Therapy,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The first Fe(III) complexes 1-6 with cyclin-dependent kinase (CDK) inhibitors of the type [Fe(L(n))Cl(3)].nH(2)O (n=0 for 1, 1 for 2, 2 for 3-6; L(1)-L(6)=C2- and phenyl-substituted CDK inhibitors derived from 6-benzylamino-9-isopropylpurine), have been synthesized and characterized by elemental analysis, IR, (57)Fe Mössbauer, (1)H and (13)C NMR, and ES+ mass spectroscopies, conductivity and magnetic susceptibility measurements, and thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The study revealed that the compounds are mononuclear, tetrahedral high-spin (S=5/2) Fe(III) complexes with an admixture of an S=3/2 spin state originating probably from five-coordinated Fe(III) ions either connecting with a bidentate coordination mode of the CDK inhibitor ligand or relating to the possibility that one crystal water molecule enters the coordination sphere of the central atom in a portion of molecules of the appropriate complex. Nearly spin-only value of the effective magnetic moment (5.82micro(eff)/micro(B)) was determined for compound 1 due to absence of crystal water molecule(s) in the structure of the complex. Based on NMR data and DFT calculations, we assume that the appropriate organic ligand is coordinated to the Fe(III) ion through the N7 atom of a purine moiety. The cytotoxicity of the complexes was tested in vitro against selected human cancer cell lines (G-361, HOS, K-562 and MCF-7) along with the ability to inhibit the CDK2/cyclinE kinase. The best cytotoxicity (IC(50): 4-23muM) and inhibition activity (IC(50): 0.02-0.09microM) results have been achieved in the case of complexes 2-4, and complexes 3, 4 and 6, respectively. In addition, the X-ray structure of 2-chloro-6-benzylamino-9-isopropylpurine, i.e. a precursor for the preparation of L(1), L(4) and L(5), is also described.

• MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• elektrochemické techniky metody   MeSH
• inhibiční proteiny cyklin-dependentních kinas * chemie   metabolismus   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• puriny chemie   MeSH
• spektrální analýza metody   MeSH
• železo chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• inhibiční proteiny cyklin-dependentních kinas * MeSH
• puriny MeSH
• železo MeSH

Selective inhibitors of kinases that regulate the cell cycle, such as cyclin-dependent kinases (CDKs) and aurora kinases, could potentially become powerful tools for the treatment of cancer. We prepared and studied a series of 3,5,7-trisubstituted pyrazolo[4,3-d]pyrimidines, a new CDK inhibitor scaffold, to assess their CDK2 inhibitory and antiproliferative activities. A new compound, 2i, which preferentially inhibits CDK2, CDK5, and aurora A was identified. Both biochemical and cellular assays indicated that treatment with compound 2i caused the downregulation of cyclins A and B, the dephosphorylation of histone H3 at Ser10, and the induction of mitochondrial apoptosis in the HCT-116 colon cancer cell line. It also reduced migration as well as tube and lamellipodia formation in human endothelial cells. The kinase inhibitory profile of compound 2i suggests that its anti-angiogenic activity is linked to CDK5 inhibition. This dual mode of action involving apoptosis induction in cancer cells and the blocking of angiogenesis-like activity in endothelial cells offers possible therapeutic potential.

• Klíčová slova
• angiogenesis, apoptosis, aurora A, cyclin-dependent kinase, inhibitor, pyrazolo[4,3-d]pyrimidine,
• MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• aurora kinasa A antagonisté a inhibitory   MeSH
• buněčný cyklus účinky léků   MeSH
• cyklin-dependentní kinasa 2 antagonisté a inhibitory   MeSH
• cyklin-dependentní kinasa 5 antagonisté a inhibitory   MeSH
• endoteliální buňky pupečníkové žíly (lidské) MeSH
• HCT116 buňky MeSH
• inhibiční proteiny cyklin-dependentních kinas chemická syntéza   chemie   farmakologie   MeSH
• inhibitory angiogeneze chemická syntéza   chemie   farmakologie   MeSH
• inhibitory proteinkinas chemická syntéza   chemie   farmakologie   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• racionální návrh léčiv MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• AURKA protein, human MeSH Prohlížeč
• aurora kinasa A MeSH
• CDK2 protein, human MeSH Prohlížeč
• CDK5 protein, human MeSH Prohlížeč
• cyklin-dependentní kinasa 2 MeSH
• cyklin-dependentní kinasa 5 MeSH
• inhibiční proteiny cyklin-dependentních kinas MeSH
• inhibitory angiogeneze MeSH
• inhibitory proteinkinas MeSH

BACKGROUND/AIM: 9-[2-(phosphonomethoxy)ethyl] guanine (PMEG) is a guanine acyclic nucleotide analog whose targeted prodrugs are being investigated for chemotherapy of lymphomas. Its antiproliferative effects have been attributed to cell cycle arrest and induction of apoptosis, however, the underlying mechanisms remain poorly understood. The objective of this study was to determine the requirements for caspase and CD95/Fas activation in PMEG-induced apoptosis. Additionally, the influence of PMEG on cell cycle regulatory proteins was explored. MATERIALS AND METHODS: CCRF-CEM cells were exposed to PMEG with/without caspase inhibitor or anti-Fas blocking antibody and assayed for phosphatidyl serine externalization, mitochondrial depolarization and the cleavage of procaspase 3 and the nuclear protein poly (ADP-ribose) polymerase (PARP). RESULTS: Despite an observed increase of caspase 3, 8 and 9 proteolytic activity, neither pretreatment of the cells with cell-permeable caspase inhibitors nor blocking the death receptor with anti-Fas antibody did prevent apoptosis induced by PMEG. CONCLUSION: PMEG-induced apoptosis is caspase- and CD95/Fas-independent.

• MeSH
• aktivace enzymů MeSH
• antigeny CD95 metabolismus   MeSH
• apoptóza účinky léků   fyziologie   MeSH
• buněčný cyklus účinky léků   fyziologie   MeSH
• cyklin E biosyntéza   genetika   MeSH
• cyklin-dependentní kinasy biosyntéza   metabolismus   MeSH
• guanin analogy a deriváty   farmakologie   MeSH
• inhibiční proteiny cyklin-dependentních kinas biosyntéza   metabolismus   MeSH
• kaspasy metabolismus   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• mitochondrie účinky léků   fyziologie   MeSH
• nádorové buněčné linie MeSH
• onkogenní proteiny biosyntéza   genetika   MeSH
• organofosforové sloučeniny farmakologie   MeSH
• S fáze účinky léků   MeSH
• signální transdukce MeSH
• T-lymfocyty cytologie   účinky léků   enzymologie   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 9-((2-phosphonylmethoxy)ethyl)guanine MeSH Prohlížeč
• antigeny CD95 MeSH
• CCNE1 protein, human MeSH Prohlížeč
• cyklin E MeSH
• cyklin-dependentní kinasy MeSH
• FAS protein, human MeSH Prohlížeč
• guanin MeSH
• inhibiční proteiny cyklin-dependentních kinas MeSH
• kaspasy MeSH
• onkogenní proteiny MeSH
• organofosforové sloučeniny MeSH

The molecular basis for the transition of carcinoma of the prostate from androgen-dependent to androgen-independent growth is largely unknown. Currently for example, it is not clear whether the androgen-independent phenotype is a result of selection of a subgroup of genetically distinct prostate tumour cells which are already hormone-resistant or a genetic adaptation of prostate tumour cells to the hormone therapy itself. It has also been established that prostate tumour transformation is a result of homeostatic control defects, a line of thinking directed toward elucidating the apoptotic profile of prostate tumour cells that may be important in determining prognosis, response to therapy and illness progression. Main consideration in this part of rewiev is given to the role of tumour suppressor genes pRb and PTEN and also the natural inhibitors of cyclin dependent kinases - proteins p21(Waf1/Cip1) and p27(Kip1). Attention is also given to the role of FAS-mediated pathways in apoptosis induction.

• MeSH
• antigeny CD95 genetika   fyziologie   MeSH
• apoptóza fyziologie   MeSH
• fosfohydroláza PTEN genetika   fyziologie   MeSH
• inhibiční proteiny cyklin-dependentních kinas genetika   fyziologie   MeSH
• lidé MeSH
• nádorové supresorové proteiny genetika   fyziologie   MeSH
• nádory prostaty genetika   patofyziologie   MeSH
• nádory závislé na hormonech patofyziologie   MeSH
• prognóza MeSH
• progrese nemoci MeSH
• proteinkinasa CDC2 genetika   fyziologie   MeSH
• retinoblastomový protein genetika   fyziologie   MeSH
• supresorové geny fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antigeny CD95 MeSH
• fosfohydroláza PTEN MeSH
• inhibiční proteiny cyklin-dependentních kinas MeSH
• nádorové supresorové proteiny MeSH
• proteinkinasa CDC2 MeSH
• retinoblastomový protein MeSH

Mammalian oocytes are arrested at prophase I until puberty when luteinizing hormone (LH) induces resumption of meiosis of follicle-enclosed oocytes. Resumption of meiosis is tightly coupled with regulating cyclin-dependent kinase 1 (CDK1) activity. Prophase I arrest depends on inhibitory phosphorylation of CDK1 and anaphase-promoting complex-(APC-CDH1)-mediated regulation of cyclin B levels. Prophase I arrest is maintained by endogenously produced cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA) that in turn phosphorylates (and activates) the nuclear kinase WEE2. In addition, PKA-mediated phosphorylation of the phosphatase CDC25B results in its cytoplasmic retention. The combined effect maintains low levels of CDK1 activity that are not sufficient to initiate resumption of meiosis. LH triggers synthesis of epidermal growth factor-like factors in mural granulosa cells and leads to reduced cGMP transfer from cumulus cells to oocytes via gap junctions that couple the two cell types. cGMP inhibits oocyte phosphodiesterase 3A (PDE3A) and a decline in oocyte cGMP results in increased PDE3A activity. The ensuing decrease in oocyte cAMP triggers maturation by alleviating the aforementioned phosphorylations of WEE2 and CDC25B. As a direct consequence CDC25B translocates into the nucleus. The resulting activation of CDK1 also promotes extrusion of WEE2 from the nucleus thereby providing a positive amplification mechanism for CDK1 activation. Other kinases, e.g. protein kinase B, Aurora kinase A and polo-like kinase 1, also participate in resumption of meiosis. Mechanisms governing meiotic prophase I arrest and resumption of meiosis share common features with DNA damage-induced mitotic G2-checkpoint arrest and checkpoint recovery, respectively. These common features include CDC14B-dependent activation of APC-CDH1 in prophase I arrested oocytes or G2-arrested somatic cells, and CDC25B-dependent cell cycle resumption in both oocytes and somatic cells.

• MeSH
• AMP cyklický metabolismus   MeSH
• anafázi podporující komplex MeSH
• Cdh1 proteiny MeSH
• cyklin B1 metabolismus   MeSH
• epidermální růstový faktor metabolismus   MeSH
• G2 fáze * MeSH
• inhibiční proteiny cyklin-dependentních kinas metabolismus   MeSH
• komplexy ubikvitinligas metabolismus   MeSH
• meióza * MeSH
• metafáze MeSH
• myši MeSH
• oocyty metabolismus   MeSH
• oogeneze * MeSH
• profáze meiózy I MeSH
• proliferace buněk * MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• signální transdukce * MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• AMP cyklický MeSH
• anafázi podporující komplex MeSH
• Ccnb1 protein, mouse MeSH Prohlížeč
• Cdh1 proteiny MeSH
• cyklin B1 MeSH
• epidermální růstový faktor MeSH
• Fzr1 protein, mouse MeSH Prohlížeč
• inhibiční proteiny cyklin-dependentních kinas MeSH
• komplexy ubikvitinligas MeSH
• proteiny buněčného cyklu MeSH

Olomoucine II is a cyclin-dependent kinase inhibitor and a potential antineoplastic agent because it can arrest animal cell cycles. This study examines its interactions with human liver microsomal cytochrome P450 (P450) enzymes. Spectroscopic and high-performance liquid chromatography (HPLC) methods were used to estimate the degree of olomoucine II-mediated inhibition of enzymatic activities of eight drug-metabolizing P450s in vitro. In addition, mass spectrometry coupled with HPLC was used to identify an olomoucine II metabolite (2,5-dihydroxyroscovitine) formed in the reaction mixtures, and CYP3A4 was found to be responsible for the hydroxylation of the N(6)-benzyl ring at position 5, leading to this compound. Olomoucine II significantly inhibited the enzymatic activities of CYP1A2, CYP2C9, and (to a lesser degree) CYP3A4. The results indicate that use of olomoucine II as a drug could affect the activities of CYP3A4, CYP1A2, and CYP2C9 in vivo. Hence, the clinical relevance of these interactions should be carefully evaluated.

• MeSH
• antitumorózní látky farmakologie   MeSH
• aromatické hydroxylasy antagonisté a inhibitory   MeSH
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2B6 MeSH
• cytochrom P450 CYP2C9 MeSH
• inhibiční proteiny cyklin-dependentních kinas farmakologie   MeSH
• inhibitory cytochromu P450 CYP1A2 MeSH
• inhibitory cytochromu P450 CYP3A * MeSH
• inhibitory cytochromu P450 MeSH
• jaterní mikrozomy účinky léků   enzymologie   MeSH
• játra cytologie   enzymologie   MeSH
• lékové interakce MeSH
• lidé MeSH
• N-demethylasy MeSH
• puriny farmakologie   MeSH
• substrátová specifita MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• aromatické hydroxylasy MeSH
• CYP2B6 protein, human MeSH Prohlížeč
• CYP2C9 protein, human MeSH Prohlížeč
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2B6 MeSH
• cytochrom P450 CYP2C9 MeSH
• inhibiční proteiny cyklin-dependentních kinas MeSH
• inhibitory cytochromu P450 CYP1A2 MeSH
• inhibitory cytochromu P450 CYP3A * MeSH
• inhibitory cytochromu P450 MeSH
• N-demethylasy MeSH
• olomoucine II MeSH Prohlížeč
• puriny MeSH

BACKGROUND: Leukemias develop due to defects in proliferation, differentiation and apoptosis, which take place in stem cells or progenitors of hematopoiesis. These processes have several crossing points, one of them is the role of inhibitors of cyclin-dependent kinases. The aim of this study was to study the expression of cyclin-dependent kinases inhibitors p21 Cip and p27 Kip and expression of proliferative antigen Ki-67 in leukocytes of human leukemia. METHODS AND RESULTS: The expression of cyclin-dependent kinases inhibitors was detected at mRNA level mainly by comparative reverse-transcription polymerase chain reaction and in selected samples also by the real-time polymerase chain reaction. While p27 Kip expression in leukocytes of leukemic patients and healthy persons was universal, large differences in expression of p21 Cip were found both among individual patients of the same type of leukemia and between different types of leukemias and healthy persons. The p21 Cip expression was significantly higher in acute leukemias than in chronic ones and healthy persons. A comparison of p21 Cip expression with the clinical outcome of the leukemic patients showed that the group of 14 acute leukemia patients surviving more than 30 months had a significantly lower expression of p21 Cip than 12 patients of this type of leukemia who died within this time limit. Moreover, the results obtained on a smaller set of acute promyelocytic leukemia patients indicated that the lower p21 expression is connected with a better prognosis. CONCLUSION: Our results pointed out the importance of the cyclin-dependent kinase inhibitor p21 Cip in human leukemias and indicated that the lower p21 Cip expression might be a positive prognostic factor in acute myeloid leukemia patients.

• MeSH
• antigen Ki-67 metabolismus   MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• cykliny metabolismus   MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• inhibitor p27 cyklin-dependentní kinasy MeSH
• inhibitory enzymů metabolismus   MeSH
• leukemie metabolismus   MeSH
• leukocyty metabolismus   MeSH
• lidé MeSH
• nádorové supresorové proteiny metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• polymerázová řetězová reakce MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen Ki-67 MeSH
• CDKN1A protein, human MeSH Prohlížeč
• cyklin-dependentní kinasy MeSH
• cykliny MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• inhibitor p27 cyklin-dependentní kinasy MeSH
• inhibitory enzymů MeSH
• nádorové supresorové proteiny MeSH
• proteiny buněčného cyklu MeSH

Normal human B lymphocytes are sensitive to the growth-inhibitory action of transforming growth factor beta1 (TGFbeta1) whereas malignant B lymphoma cells are mostly resistant to TGFbeta1 effects. We examined the phosphorylation status of retinoblastoma protein and the activity of G(1) cyclin-dependent kinases (cdk) in TGFbeta1-sensitive malignant follicular lymphoma cells during the TGFbeta1 treatment. The kinase activity of cdk2, cdk4, and cdk6 was significantly reduced and hypophosphorylation of pRb on serine 795 (S795) and threonine 373 (T373) was observed. We examined the composition of cdk complexes and the level of cdk inhibitors to explain the inhibitory action of TGFbeta1 toward cdk activity. Both cdk4 and cdk6 were notably dissociated from cyclin D cofactors, while cyclin E-cdk2 complexes remained coupled in TGFbeta1-treated cells. TGFbeta1-induced growth arrest was associated with notably increased binding of p21(WAF1) to cdk4 and cdk6. No induction of cdk-inhibitor molecules of INK family was observed in TGFbeta1-treated DoHH2 cells. As shown, TGFbeta1-induced growth arrest of malignant B cells was associated with the activation of CIP/KIP family members of cdk inhibitors.

• MeSH
• aktivace enzymů MeSH
• buněčné dělení MeSH
• cyklin D MeSH
• cyklin-dependentní kinasa 4 MeSH
• cyklin-dependentní kinasa 6 MeSH
• cyklin-dependentní kinasy chemie   metabolismus   MeSH
• cykliny chemie   metabolismus   MeSH
• fosforylace MeSH
• G1 fáze MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• lidé MeSH
• lymfom metabolismus   MeSH
• nádorové buňky kultivované MeSH
• protoonkogenní proteiny * MeSH
• retinoblastomový protein metabolismus   MeSH
• transformující růstový faktor beta metabolismus   MeSH
• transformující růstový faktor beta1 MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CDK4 protein, human MeSH Prohlížeč
• CDK6 protein, human MeSH Prohlížeč
• CDKN1A protein, human MeSH Prohlížeč
• cyklin D MeSH
• cyklin-dependentní kinasa 4 MeSH
• cyklin-dependentní kinasa 6 MeSH
• cyklin-dependentní kinasy MeSH
• cykliny MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• protoonkogenní proteiny * MeSH
• retinoblastomový protein MeSH
• TGFB1 protein, human MeSH Prohlížeč
• transformující růstový faktor beta MeSH
• transformující růstový faktor beta1 MeSH

BACKGROUND: Transforming growth factor beta1 (TGFbeta1) induces growth arrest in many cell types, including B lymphocytes. The inhibitory action of TGFbeta1 is mediated by the deactivation of kinase complexes. The cell-cycle engine is tightly controlled by cyclin-dependent kinase (cdk) inhibitors, which mediate extracellular negative signals, resulting in cell-cycle arrest at different G1 points. MATERIAL/METHODS: Our experimental DoHH2 cell line model was derived from a patient with malignant non-Hodgkin's lymphoma (NHL) of follicular origin. We examined the effect of TGFbeta1 on the expression and phosphorylation of key cell-cycle regulators by immunoprecipitation and immunoblotting. RESULTS: After 48 hours of TGFbeta1 (10 ng/ml) treatment, a significantly increased number of DoHH2 cells was retained in G0/G1 phase. Our results showed the inhibitory action was associated with hypophosphorylation of pRb on serine 795 (S795) and threonine 373 (T373). We examined the composition of the cdk complexes and the level of cdk inhibitors to explain the inhibitory action of TGFbeta1 on cdk activity. Western blotting showed that the total level of the kinase inhibitor p21 (WAF1) increased after TGFbetal treatment. Our results indicate that a notably high level of p21(WAF1) was bound to cdk4/6 due to the treatment and that the binding of p21(WAF1) was associated with cyclin D-cdk4/6 complex decomposition. CONCLUSIONS: Our investigation of the effect of TGFbetal on cell-cycle progression of a non-Hodgkin's lymphoma cell line of follicular lymphoma subtype showed that the TGFbeta1-induced growth arrest of malignant B cells was associated with the activation of CIP/KIP family members of cdk inhibitors.

• MeSH
• B-buněčný lymfom metabolismus   MeSH
• buněčný cyklus účinky léků   MeSH
• folikulární lymfom metabolismus   MeSH
• fosforylace MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• transformující růstový faktor beta farmakologie   MeSH
• transformující růstový faktor beta1 MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• proteiny buněčného cyklu MeSH
• TGFB1 protein, human MeSH Prohlížeč
• transformující růstový faktor beta MeSH
• transformující růstový faktor beta1 MeSH