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Cell Cycle Regulation

Date: 10. April 2018            

Cell Cycle Regulatory Proteins
Sqadia video is the demonstration of Cell Cycle Regulation. Protein Kinase and protein phosphatases, Ubiquitin Ligases and Their Activators, and Gene Regulatory Proteins are Major Cell Cycle Regulatory Proteins that modify Cdks. Cdk-activating kinase (CAK) Phosphorylates an activating site in Cdks. Weel Kinase, phosphorylates inhibitory sites in Cdks primarily involved in controlling entry into mitosis. Cdc25 Phosphatase removes inhibitory phosphates from Cdks. Cdc20 is APC-activating subunit in all cells; triggers initial activation of APC at metaphase-to-anaphase transition; Stimulated by M-Cdk activity. p53 Promotes transcription of genes that induce cell cycle arrest.

Regulation of Kinase Activity
Cdc25 and Wee1 have opposing effects on S. pombe MPF activity. Cells that lack Cdc25 or Wee1 activity, as a result of recessive temperature sensitive mutations in the corresponding genes, have the opposite phenotype. Likewise, cells with multiple copies of plasmids containing wild-type cdc25 or wee1, and which thus produce an excess of the encoded proteins, have opposite phenotypes. These phenotypes imply that the mitotic cyclin CDK complex is activated by Cdc25 and inhibited by Wee1. Interaction of mitotic cyclin (Cdc13) with cyclin-dependent kinase (Cdc2) forms mitosis-promoting factor (MPF). The CDK subunit can be phosphorylated at two regulatory sites: by Wee1 at tyrosine-15 (Y15) and by CDK-activating kinase (CAK) at threonine-161 (T161). Removal of the phosphate on Y15 by Cdc25 phosphatase yields active MPF in which the CDK subunit is monophosphorylated at T161. In a Model for control of entry into anaphase by APC-regulated degradation of the cohesion link between sister chromatids. The multiprotein cohesion complex contains SMC1 and SMC3, dimeric proteins that bind DNA of each sister chromatid through globular domains at one end. Scc1 and two other cohesin subunits bind to the SMC proteins associated with each chromatid, thus crosslinking the chromatids. Three G1 Cyclins Associate with S. cerevisiae CDK to form S Phase–Promoting Factors.

Control of G to S Transition
Genes encoding two S. cerevisiae G1 cyclins were identified by their ability to supress a temperature-sensitive mutant CDK. This genetic screen is based on differences in the interactions between G1 cyclins and wild-type and temperature-sensitive (ts) S. cerevisiae CDKs. Wild-type cells produce a normal CDK that associates with G1 cyclins, forming the active S phase–promoting factor (SPF). Some cdc28 ts mutants express a mutant CDK with low affinity for G1 cyclin at 36°C. These mutants produce enough G1 cyclin-CDK (SPF) to support growth and colony development at 25 C, but not at 36 C. When cdc28 ts cells were transformed with a S. cerevisiae genomic library cloned in a high-copy plasmid, three types of colonies formed at 36 C.  Control of the G1 → S phase transition in S. cerevisiae by regulated proteolysis of the S-phase inhibitor Sic1. The S-phase cyclin-CDK complexes (Clb5-CDK and Clb6-CDK) begin to accumulate in G1 but are inhibited by Sic1. This inhibition prevents initiation of DNA replication until the cell is fully prepared.  During early G1, unphosphorylated replication initiation factors assemble on an origin-recognition complex (ORC) bound to a replication origin to generate a pre-replication complex. In the S phase, S-phase cyclin-CDK complexes and DDK phosphorylate components of the pre-replication complex. This leads to binding of Cdc45, activation of the Mcm helicases, which unwind the parental DNA strands, and release of the phosphorylated Cdc6 and Ctd1 initiation factors. RPA binds to the resulting single-stranded DNA.

Cell Cycle Checkpoint Control
In the current model for regulation of the eukaryotic cell cycle, passage through the cycle is controlled by G1, S-phase, and mitotic cyclin-dependent kinase complexes. These are composed of a regulatory cyclin subunit and a catalytic cyclin-dependent kinase (CDK) subunit. Two ubiquitin ligase complexes (orange), SCF and APC, polyubiquitinate specific substrates including S-phase inhibitors, securin, and mitotic cyclins, marking these substrates for degradation by proteasomes. Proteolysis of the S-phase inhibitor activates S-phase cyclin-CDK complexes. The unreplicated-DNA checkpoint prevents activation of cyclin A-CDK1 and cyclin B-CDK1. In the spindle-assembly checkpoint, Mad2 and other proteins inhibit activation of the APC specificity factor (Cdc20) required for polyubiquitination of securin, thereby preventing entry into anaphase. In S. cerevisiae, Cdc14 phosphatase activity is required for the exit from mitosis. During interphase and early mitosis, Cdc14 is sequestered and inactivated in the nucleolus.

Programmed Cell Death
Programmed cell death is as needed for proper development as mitosis is. CASPASES are synthesized in cell as inactive precursors, or PROCASPASES, which are usually activated by cleavage at aspartic acids by other caspases. CASPASES stands for cysteine-dependent asparate-specific proteases. There are two pathways for activation of apoptosis, one is Extrinsic pathway i.e. Activaion of apoptosis from outside the cell, and the other is intrinsic pathway i.e. activaation of apoptosis from inside the cell.

Hashmi, Uzair
  • Academics: MS
  • Specialization: Nanomedicine
  • Current: Researcher
  • University: NUST
  • Location: Islamabad, Pakistan
  • Clinical / Teaching Years: 6 / 3
  • Course: Cell Biology
  • Course: Physiology

Mr. Uzair Hashmi secured his Bachelors in Applied Biosciences and Masters in Industrial Biotechnology with specialization in Nanomedicine from National University of Science and Technology (NUST)

Based on his bachelor's project he laid down the foundation of Pakistan's first disinfectant based startup Nanosmart and secured seed funding of 0.1 million. Startup got recognition in United nations Industrial development organization platform. 

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