The Cell Cycle: A Deep Dive

The Cell Cycle

Ayush Noori | EduSTEM Advanced Biology

Interphase and Mitosis:

  • The cell cycle is the life of a cell from the time it first form during division of a parent cell until its own division into two daughter cells.
  • Somatic cells are diploid and have 46 chromosomes in humans, unlike the reproductive cells, or gametes , which are haploid and have 23 chromosomes in humans.
    • In somatic cells, the division of genetic material in the nucleus is called mitosis .
  • The mitotic (M) phase is usually the shortest part of the cell cycle, and alternates with a much longer stage called interphase, which is divided into three phases.
    • During the first G1 phase , the cell prepares to divide by growing, producing proteins, and duplicating cytoplasmic organelles.
    • The DNA divides during the second S phase .
    • The cell continues to grow during the third G2 phase , which directly proceeds mitosis.
    • Image Credit: “The Cell Cycle: Figure 1” by OpenStax College, Biology (CC BY 3.0).

This extension explores the molecular pathways which regulate mitosis, specifically in epidermal and epithelial cells.

Kandasamy K, Mohan SS , Raju R, et al. NetPath: A public resource of curated signal transduction pathways. Genome Biol. 2010 Jan 12;11(1):R3. doi: 10.1186/gb-2010-11-1-r3.

Please see the above link for a comprehensive diagram of the epidermal growth factor receptor (EGFR) signaling pathways. Below is an excerpt from WikiPathways which elaborates on this:

“Epidermal growth factor receptor (EGFR) also known as ErbB1/HER1 is a member of the ErbB family of receptor tyrosine kinases, which also includes ErbB2 (Neu, HER2), ErbB3 (HER3) and ErbB4 (HER4). Several ligands such as epidermal growth factor, transforming growth factor-alpha, epigen, amphiregulin, betacellulin, heparin-binding EGF and epiregulin are known to specifically bind to EGFR. Epidermal growth factor (EGF) is one of the high affinity ligands of EGFR. EGF/EGFR system induces growth, differentiation, migration, adhesion and cell survival through various inter-acting signaling pathways. The binding of EGF to the extracellular domain of EGFR induces the dimerization, activation of intrinsic kinase activity and subsequent autophosphorylation of EGFR at multiple residues in the cytoplasmic region such as Tyr 1092, Tyr 1172, Tyr 1197, Tyr 1110, Tyr 1016). Activated EGFR recruits various cytoplasmic proteins which transduce and regulate the EGFR function. The proteins recruited to active EGFR include many Src homology 2 (SH2) and phosphotyrosine binding (PTB) domain containing proteins which binds to the tyrosine phosphorylated residues in EGFR, enzymes which act on EGFR and also various EGFR substrates. One of the adapter proteins, GRB2, binds to the phosphotyrosine residue at 1068 and recruits SOS to the membrane. SOS activates GDP/GTP exchange which recruits RAF to the membrane. RAF phosphorylates MEKs, which then activates the extracellular signal regulated kinase (ERK). ERK activates a number of transcriptional regulators to induce cell growth and proliferation.

Specifically, ERK2 (also known as MAPK) activates the Cyclin D and Cyclin-Dependent Kinase (CDK) 4/6 signaling pathway. Increased intracellular concentration of CDK4/6 causes the phosphorylation of retinoblastoma protein (pRb). Hypophosphorylated pRB sequesters E2F, therefore phosphorylating pRB releases E2F. The nuclear localization signal of E2F is then bound by the karyopherin importin-β and transported into the nucleus (using the RanGTP gradient), where it acts as a transcription factor to ultimately stimulate the transition from the G1 phase to the S phase and DNA replication.

Wee P and Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers 2017, 9(5), 52. doi: 10.3390/cancers9050052.

Please click on the above link and see Figure 1 for a diagram which depicts the entire process.

“Epidermal growth factor receptor (EGFR) signaling pathways leading to G1/S cell cycle progression activated by EGF activation. Depicted are the RAS-RAF-MEK-ERK MAPK and PI3K-AKT-mTOR pathways. EGF activation of the EGFR induces receptor dimerization and transphosphorylation of the C-terminal domain. The phosphorylated C-terminal domain binds SHC and GRB2, along with PLC-γ1 at Y992 (not pictured). The GRB2 SH3 domain recruits the proline-rich domains of SOS or GAB1 to initiate ERK MAPK or AKT signaling respectively. SOS is also recruited to the plasma membrane (PM) by the interaction of its PH (pleckstrin homology) domains with PIP2 (phosphatidylinositol-4,5-bisphosphate) and PA (phosphatidic acid). SOS catalyzes the conversion of GDP to GTP of RAS. Active RAS uses its RAS RAF-binding domain (RBD) to recruit RAF-1. RAF-1 is activated by dephosphorylation and phosphorylation events, and activates MEK1/2. Activated MEK1/2 activates ERK1/2. ERK1/2 has various cytoplasmic and nuclear targets, which aid in the transcription and translation of Cyclin D1. For example, ELK-1 transcribes the c-FOS gene (not pictured), and the protein product together with c-JUN make up the AP-1 complex. The AP-1 complex as well as c-MYC induce the transcription of CYCLIN D1. Increased levels of CYCLIN D1 correlates with increased CDK4/6 activity, which phosphorylates RB. Phosphorylated RB releases the E2F transcription factor, which participates in the transcription of Cyclin E and leads to G1/S progression.

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Best Regards,

Ayush Noori

EduSTEM Boston Chapter Founder


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