Molecular Cell Biology Spring 2014, Michael Pavlov To read: relevant parts from chapters 20 and 25.

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1 Molecular Cell Biology Spring 2014, Michael Pavlov To read: relevant parts from chapters 20 and 25. Lecture 10: Initiation of the Cell Cycle and its aberrations. Cip/Kip and Ink4 brake the cell cycle Inhibition of the Cell Cycle progression Activators of the Cell Cycle Initiation p53 as a tumor suppressor p53 and apoptosis Details of apoptosis Senescence Experimental Studies of the Cell cycle

2 Inhibition of Cell Cycle Initiation. Activation of CycD-CDK4/6 is pivotal in the initiation of cell cycle. This Cyc-CDK complex are inhibited by Ink4 inhibitors: p16, p15 and others A big picture: the map shows how the cell cycle entry program can be activated or inhibited in the response to external stimuli. Cancer can be viewed as the execution of the cell cycle program independently of external signals. TGF signaling keeps cells in G1 by directly inducing Ink4 (p15) and Kip/Cip (p27) transcription

3 Kinase activation in Cyc-CDK complex by T-loop (T160) phosphorylation and Cyc-CDK complex inhibition by p27cip The role of CAK phosphorylation in the organization of active center (100 fold activation). Only N-terminal inhibitory domain of the inhibitor is crystallized in the complex with Cyc-CDK P27 interacts both with K2 and Cyc parts In the case of K4 CycD complex, p27 stabilizes this complex and can also activate it in proliferating cells (to be explained later)

4 p27cip blocks ATP binding by the CycA:CDK2 complex completely blocking the kinase activity P27 has 105 additional residues following the inhibitory domain, while p21 and p57 have 82 and 220 additional AAs, respectively. These additional residues belong to the core of proteins supporting the structure of the inhibitory domain in the Cyc-CDK absence. LFGPV sequence in the coil section of Kip/Cip initiates the binding to the Cyc moiety.

5 P21Cip and p27kip not only controls the cell cycle progression. Together with other inhibitors they control its initiation Cyc-CDK complex phosphorylates Rb which leads to the functional deactivation of Rbs and activation of transcription cascade (including the E2F and CycE transcription) that leads to the S- phase commencement. Cyclin D synthesis is the major entry road into the cell cycle and overexpression of CycD is observed in many cancers.

6 Ink4 inhibitors have a different mode of action: Ink4 binding prevents CycD binding to CDK4/6 and may distort CycD-CDK4/6 complexes making them inactive. Ink4 binding displaces KIP/CIP from CDK4 and CDK6. Ink4 and Kip/Cip have completely different structures Ink4-inihibitor structure: P16 has 4 and p19 5 ankyrin repeats

7 Kip/Cip and Ink4 control Mitogenic stimuli that lead to the expression of cyclin D and Cdk4 result in phosphorylation of the CycD- Cdk4 major target: the Rb proteins. This relieves inhibition of the ClnE-CDK2 and E2F transcription, promoting the entry into the cell cycle. The control of the general p21cip and p27kip Cln- CDK inhibitors and the INK4 inhibitors of Cdk4/6 are among the most important points of the control of cell cycle progression. p21cip (WAF1), p27kip and p57kip inhibitors of ClnE/A-CDK2 complexes bind also tightly to CycD- CDK4/6 complexes but without inhibiting them, so that CycD-CDK4 actually sequester p27kip in the cell preventing its interaction with ClnE-CDK2. In contrast, INK4-type inhibitors: p16-ink4a, p15- INK4b, p18 (Ink4c) and p19 (Ink4d) blocks CnD- CDK4 complex formation. Besides inhibiting Cdk4/6 directly, the binding of INK4 displaces p27kip from CycD-CDK4 complexes which increases the p27kip block of ClnE-CDK2. Importantly, mitogen withdrawal before the restriction point (late G1) is passed results in cycling D degradation. This will also lead to the release of p27kip and p21cip from CycD-CDK4/6 complexes to inhibit ClnE-CDK2 more efficiently

8 Affinities of p21 and p27 to different Cyc:CDK complexes (The smaller Ki the higher the affinity). Ki values for for 50% inhibition of Cyc-CDK by p21 and p27 D-K4 E-K2 A-K2 B-K1 P nm 3.7 nm 0.5 nm 400 nm P nm 0.3 nm Why then p27 presence does not inhibit D-K4 complexes?? Explanation: Two different forms of p27: P-Y88 form (by a Tyr-kinase) can bind to D-K4 and stabilize it but does not block its activity. But P-Y88 p27 inhibits E-K2. Proliferating cells have the P-Y88 form. Non-phosphorylated Y88 form of p27 inhibits both D-K4 and E-K2. Phosphorylated P-T186 p27 (by E-K2) is the SCF substrate (Ubiquitinylated and degraded) Ink4a,b (p15, p16) binding displaces p27 directing p27 to E-K2 inhibition

9 GTFb controls Myc and Ink4b expression Even if the production of CycD is activated, the cell proliferation is still under control of cell cycle inhibitors that are in turn under control of the SMAD transcription factors. SMADs are activated by anti-proliferation signals coming through TGF- R. Ironically, the signals conducted through these so called Transforming Growth Factor Receptors are in fact halt most cells before the passage through the restriction point. The cell cycle entry is repressed here through the Smad3 activated by the TGFb receptor. Activated Smad3 forms a complex with Smad4 plus E2F4/5-DP1 and co-repressor prb (p107 in this case). This complex binds to a composite Smad3/E2F (E-box) site in the promoter of Myc TF and blocks Myc transcription. This leads to low Myc levels. Myc-Myz1 complex represses p15ink4b expression. So, in the absence of Myc the p15 promoter is de-repressed. Transcription of p15 is activated by Sma3/Smad4 with the help of Foxo transcription factor (regulated by Akt). p15/ink4b expression blocks the entry into the cell-cycle. The same type of regulation works also for p21cip inhibitor of cell cycle.

10 Generally, proteins which expression inhibits cell proliferation are classified as tumor suppressors while those which promote cell proliferation are called pro-oncogenes. According to this classification INK4 inhibitors are certainly tumor suppressors along with other components that promote their expression (like Smad3 and TFGbR). In this classification, Myc TF that inhibits the production of INK4 inhibitors by forming a complex with Miz-1 transcription factor should be classified as pro-oncogenic. We will later see that it is one of the key pro-oncogenes in the cell.

11 RB transcriptional suppressors are pure tumor suppressors. It is not surprisingly therefore that loss of function RB mutations are often found in many cancers. Individuals with hereditary retinoblastoma have only one copy of RB gene in their genome. They will inevitably acquire retinoblastoma.

12 Destruction of Skp2 in G1 by APC is instrumental to keep SCF away from p27kip to limit cell cycle progression. Thus, the activity of APC-Cdh1 is important for keeping the cells in the G1 phase. APC also degrades Cdc25 preventing the Cdk activations. SCF driven destruction of Myc and Jun TFs is important to prevent cell-cycle reentry after mitosis.

13 Oncogenic potential of different SCF specificity factors: Skp2 is clearly oncogenic since its overproduction would target Cln-CDK inhibitors (CKI). Skp2 is mainly expressed in earlier S where it participates in CycE-CDK2 activation by p27kip destruction. Skp2-SCF complex targets mainly inhibitory molecules of the cell cycle: the Cyc-CDK inhibitors p27kip, p21cip and p57cip. Fbw7 is a tumor suppressor. Fbw7-SCF targets mainly activators of the cell cycle: especially CycE and transcription factors Myc, Notch and Jun. b-trcp ubiquitinylates both activators and inhibitors of Cln-CDK complexes. b-trcp-scf ubiquitinylation of Wee1 (Swe1 in SC yeast), Cdc25 (Mih1 in SC yeast) and Emi1 are crucial for the entry into mitosis.

14 Mutations leading to reduced Ink4a, p27kip, prb levels or increased ClnE1 and CycD levels are especially bad. p27kip is haplo-insufficient, meaning that low p27kip1 level promote cell transformation. Mutated or differently expressed cell cycle components (KIP1=p27, INK4A=p16) that are present in more that 10% cases for a particular cancer are shown. >80% or >90% means % of cases when any of them is found

15 Initiation of cell cycle through MAPK pathways. Mitogens acting through Ras and Rac pathway activate Erk and Jnk. Jnk phosphorylates Jnk phosphorylates Jun and Erk phosphorylate Fos. This stabilizes Fos TFs which make AP-1. Erk also phosphorylates Elk1 in TCF leading to Fos expression. Activated Ap-1 activates Myc production. Erk2 phosphorylation of Myc on S62 activates and stabilizes Myc TF. Myc TF activates transcription of CycD. Fra-1 belongs to Fos family

16 Activation of Cell Cycle Initiation. So, how the CycD production is normally initiated? The Ras/Raf and PI3K pathways of the CycD activation are particularly important. ERK kinase is the main executor kinase of the Ras pathway. It phosphorylates and stabilize the principle factor cmyc TF that activates D-cyclin transcription. Parallel activation of Akt kinase is also pivotal for the cell cycle progression. Akt inhibits GSK3 kinase preventing it from phosphorylating CycD and Myc. When phosphorylated by GSK3, CycD and Myc can be ubiquitinylated and degraded. Akt phosphorylation inhibits FOXO (Fork Head) transcription factors causing FOXO binding to and its movement out of the nucleus preventing transcriptional activation of p27kip and p21cip. Akt activates mtor kinase

17 Myc TF structure and its binding partners. Myc dimerises with its Max partner and binds to the E-box on the DNA containing CACGTG sequence. The tans-activation NTD contains the binding site for Myc co-activator TRRAP which forms complexes with proteins with HAT activity. Myc is one of the major oncogenic proteins in the cell because Myc with its partner Max drives the CycD (CCND2 gene) and CDK4 (CDK4 gene) transcription (a). Myc:Max in complex with Miz-1 inhibit Ink4b(CDKN2B gene) and p21 (CDKN1A gene) transcription as discussed previously (b). Myc binds to enhancers and activates transcription by chromatin acetylation and remodeling. Another protein of Myc family, Mad, antagonizes Myc function by binding to the E- box in complex with Max and recruiting HDACs. Mad:Max blocks terminal differentiation

18 Akt-dependent activation of cell cycle. Akt suppresses apoptosis directly by phosphorylating and inhibiting pro-apoptotic BAD and indirectly by preventing FOXO-dependent expression of pro-apoptotic BIM. Through Akt, IKK activated NF-kB to induce expression of BclXL apoptotic suppressor to preserve mitochondria and IAPs to inhibit caspases. Akt also activates mtor kinase, which leads to up regulation of protein synthesis.

19 Limiting G1 progression. TGF-b-receptors limit cell proliferation through the SMAD node. Activated SMADs in complex with FOXO TFs promote transcription of p21cip1 and p15(ink4b) as discussed above. They also inhibit expression of Myc TF and ID (Inhibitors of Dna binding) transcription factors. ID transcription factors block terminal cell differentiation by inhibiting differentiation transcription factors like E2A from binding to DNA Many components of SMAD pathway are deregulated in cancers. FOXO transcription factors. Starvation and oxidative stress inhibit G1/S transition mainly by means of FOXO (Fork Head) transcription factors. Activation of FOXO promotes p21cip and p27kip expression as well as pro-apoptotic proteins Bim and FasL. FOXO are mainly induced by oxidative stress and starvation. Activating acetylation of FOXO is opposed by Sir2 and other HDACs

20 Oncogenic stress can be contained: Ras excess activates ETS transcription factors (Ets-1) that increase p16 transcription. But ID factors may prevent this. Myc excess activates ARF stabilizing p53 and activates Bax expression Bax makes pores in mitochondrion leading to apoptosis

21 p53 is most frequently mutated tumor suppressor Why does cancer require several mutations? Ras hyper-activation is held partially in check by Ras induced p16ink4a expression through the activation of ETS transcription factors. This will block Cdk4 and slows down cell proliferation considerably. Myc overexpression leads to Arf14 overproduction. ARF inhibits MDM2/HDM2 that controls p53 ubiquitinylation effectively increasing p53 concentration. High p53 concentrations would activate p21cip production and induce apoptosis. Thus, also the Myc oncogenity is counteracted by p53. The cells with problems in either Ras or Myc pathways will either stop proliferating due to the p16 overexpression in RasD (Ras- Dominant) cells or commit apoptosis upon uncontrolled Myc overexpression. In addition, RasD cells will also stabilize Myc through the ERK pathway, which will also bring them to apoptosis through the Myc activation. Thus, these cells can not proliferate uncontrollably. However, the second mutation inactivating p53 would block the p53 road to apoptosis allowing the cell with RasD or other mutation to survive and proliferate. When RasD mutation is introduced in the cells with the loss of function mutations in either p53 or parf14 the cells with double RasD/p53 mutations will undergo transformation. Note that parf14 mutation up-regulates the MDM2 p53 ubiquitinylase effectively eliminating p53 activity. This explains why p53 mutations are so common in human cancers. If a Myc overproducing cell acquires the secondary p53 mutation the result will be the same - cell transformation.

22 Apoptosis Apoptosis is a process in which the cell is disassembled in a calm and orderly manner so that it does not destroy or poisons its surrounding. The resulting cell debris is removed by phagocytosis. Apoptotic death is opposite to necrotic death. Necrosis results in the cell membrane rapture and release of the cell content inside tissue which invariably leads to the tissue inflammation, the hallmark of immune response. In contrast, apoptotic cells do not release their protein/dna content and do not cause immune response. Two pathways to the cell death. The extrinsic pathway takes signals from death-receptors and activates Csp8. Csp=Caspase=Cystein protease that cleaves its substrate after Asp. The extrinsic cell apoptotic signals involve trimetric death receptors. The death ligand binding is followed by the adaptor -FAS Associated Death Domain protein FADD)- binding to the cytosolic domain of the receptor. After this FADD binds the initiator caspase procaspase 8 forming the DISK (Death Inducing Signaling Complex) complex in the cytoplasm. DISK activates Csp8 that activates the executioner Csp7. Death receptor pathway activates also the intrinsic pathway through the BID activation. The intrinsic pathway: The key event in apoptosis is the release of cytochrome C (cytc) from the inter-membrane space of MH.

23 Apoptosome formation from Apaf1 is initiated by cytochrome C release from mitochondrion (MH). Upon the release from MH cytochrome C (CytC) binds to Apaf1. After ATP hydrolysis APAF1-CytC converts into semi-open form which can form active apoptosome upon ADT/ATP exchange. Active apoptosome uses its 7 CARD domains to bind monomeric Csp9 but it does not cleave it. Instead it enforces Csp9 dimerization in the center of apoptosome which makes Csp9 active. Active Csp9 initiate the activation of the caspase cascade by their cleavage. Activation results from the cleavage between the p20 and p10 caspase domains. Csp9 CARD domain interacts with Apaf1 CARD domain

24 Induction of apoptosis Anti-apoptotic MH membrane proteins like BCL-2 or BCL-XL inhibit BAK/BAX channel formation and block apoptosis. On the apoptosis induction, BH3- only proteins bind to BCL-2 like proteins promoting BAK release from their inhibition. Pro-apoptotic proteins BAX and BAK oligomerize on the MH surface enforcing the formation of pores in the outer MH membrane. The pores allow CytC (and other proteins) to escape into the cytoplasm. BH3-only proteins promote apoptosis by using their BH3 domain to directly bind to antiapoptotic BCL-2 proteins.

25 During onset of apoptosis promoted by BH3-only proteins several different molecules are released from MH (Mitochondria) is addition to CytC. Those are mainly pro-apoptotic. SMAC can bind IAPs and block them from inhibiting both the effector and execution caspase. Different IAPs in mammals: Csp9 is mainly inhibited by XIAP. All IAPs contain BIR1 domains that binds to caspases and inhibits their activity. SMAC bind to BIR3 domain of some IAPs, like XIAP, blocking their interactions with caspases. HTRA2 released from MH is a protease that cleaves IAPs. AIF is cleaved by proteases and moves into the nucleus where it causes chromosome condensation.

26 Consequence of caspase activation. The hallmark of apoptotic cell is the fragmentation of its nucleus and DNA hydrolysis in 200 bp fragments corresponding to nucleosomes. The ER and Golgi become fragmented. MHs also become fragmented, which is accompanied by the release of CytC and other proteins. Caspases cleave many of the components of the cytoskeleton: actin, actin-associated filaments, MAPs (Microtubule Associated Protein), IF-s (Intermediate Filaments) like vimentin, keratins and nuclear lamins. Csp3/7 cleave ROCK1 kinase and constitutively activates it. The cleaved ROCK1 phosphorylate myosin light chains causing actin bundle contraction. This leads further to cell membrane blebbing and the loss of water and salts from the cytoplasm. After this the cell becomes small and can be engulfed by macrophages. Fragmentation of the nucleus relies on disintegration of the nuclear lamina due to proteolysis of lamins. Proteolysis of MST1 kinase results in its translocation into the nucleus where it causes the phosphorylation of H2B histone and chromatin condensation before the chromatin degradation. ICAD cleavage releases CADs (Caspase Activated DNAse) that fragment chromatin into nucleosomes. Several components of cell-cell adhesion junctions are cleaved by caspases: cathenions and cadhedrins plus desmosonmes are cleaved. Several transcription factors like NFAT, NFkB etc. are cleaved alone with initiation factors eif2, eif3 and eif4 components. This blocks translation and transcription during apoptosis. Caspases cleave also a lot of other proteins in the cell: more than 400 protein substrates have been so far identified.

27 p53 and apoptosis. Normally, in response to an intermediate level of DNA damage the ATM/Chk2 pathway double phosphorylates p53 transcription factor and stabilizes it against MDM2 ubiquitinylation. Doubly P p53 elicits transcription of p21cip inhibitor blocking Cln- CDK complexes and arresting the cell cycle either at G1/S or at G2/M transition. Continues activation of the ATM pathway due to a high level of DNA damage leads to the opening of the apoptotic pathway of p53. This pathway is characterized by a more extensive p53 modifications: by the p53 phosphorylation on S46 in addition to the S15 and S20 phosphorylations done by ATM/Chk2. This S46 phosphorylation is done by HIPK2 kinase that becomes activated upon ATM phosphorylation of the HIPK2 inhibitor, Siah1. This S46 phosphorylation occurs in the so called PML bodies where p53, HIPK2 and CBP co-localize. The role of HAT CBP here is to acetylate Lys382 of p53. P3Ac-p53 (phosphorylated and acetylated p53) can then activate transcription of PUMA and NOXA genes which results in the production of pro-apoptotic BH3- only PUMA and NOXA proteins. In addition, P53 also up regulates the APAF1 transcription. P3Ac-p53 cooperates also with other transcription factors, like c-myc to promote synthesis of pro-apoptotic BAX.

28 Senescence: half-death Observation: Cell cultures divide for generation and then stop (Hayflick discovery)

29 Unusual Arf-Ink4 locus under ETS control Arf14 and p16 have a common exon 2 but added in different frames to their specific exon 1 Arf14 and p16 have a completely different AA-sequence The locus becomes de-repressed with cell aging: Ets1 TF increases, Bmi1 component of polycomb decreases

30 SAHF: Senescence Associated Heterochromatin Foci: H3K27 methylation Stop of the cell cycle after M by ROS-PKC

31 Experimental Studies of the Cell cycle: MPF regulation (Wee1 and Cdc25) from SP studies. SP (pombe) yeast gave insights in inhibition/activation of CDK in MPF (Mitosis Promoting Complex). In SP yeast CDK1 is called Cdc2 and ClnB is Cdc13. This organism looks like E.coli. It is unusual in that its major growth occurs in G2, after the DNA synthesis in the S-phase. This allowed a study of the factors important for the entry into mitosis. Mutations in the cell cycle genes (cell division cycle, CDC) in SP yeast are easily recognized by visual inspection since SP mutants have characteristic shapes. Two ts mutation in Cdc2 were found: one leading to extra long cells with non-divided nucleus (cdc2-) and another to small divided cells (cdc2d) at a nonpermissive temperature. In the first case Cdc2 was inactive while in the second Cdc2 was too active, leading to a premature mitosis. The wild type cdc2+ gene was identified by complementation. Its sequencing showed that it coded for a 34 kd protein homologous to eukaryotic PKs. Moreover, a human CDK1 gene (with 63% homology to Cdc2) could complement cdc2- mutations, which showed the universality of CDK1. Further studies identified Cdc13 as a mitotic cyclin. It was also shown that its concentration rose on the onset of mitosis and felt on the mitotic exit.

32 Next, a cdc25- mutant unable to enter mitosis, which phenotypically looked like a cdc2- mutant was found. On the over-production of the Cdc25 protein from a plasmid, cells looked like Cdc2D mutants. Also, mutations in yet another gene had opposite effect to that of Cdc25 mutations: wee1- resulted in premature mitosis while wee1+ over-expression blocked the mitotic entry. Since Cdc2 and Cdc13 in those cells were of wild type, one conclusion was that Wee1 deactivated MPF and Cdc25 activated MPF. The Wee1 and Cdc25 proteins were isolated and shown biochemically to be the MPF kinases (Wee1) that phosphorylated Y15 of Cdc2 (=CDK1) and the Cdc2 phosphotase (Cdc25) that removed the very same phosphate from P-Y15. Later, a different protein kinase, CAK that phosphorylated MPF on T161 and activated MPF in the absence of Y15 phosphorylation was isolated. These discoveries led to the above model of MPF activation/deactivation by Wee1 and Cdc25 as well as of MPF independent activation by CAK (Cdk Activating Kinase):

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