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General Strategy of The Cell Cycle

The cell cycle consists of four distinct phases: G1 phase, S phase (synthesis), G2 phase (collectively known as interphase) and M phase (mitosis). M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's chromosomes are divided between the two daughter cells, and cytokinesis, in which the cell's cytoplasm divides in half forming distinct cells. Activation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase.






Gap 0


A resting phase where the cell has left the cycle and has stopped dividing.


Gap 1


Cells increase in size in Gap 1. The G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis.



DNA replication occurs during this phase.

Gap 2


During the gap between DNA synthesis and mitosis, the cell will continue to grow. The G2 checkpoint control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide.

Cell division



Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells. A checkpoint in the middle of mitosis (Metaphase Checkpoint) ensures that the cell is ready to complete cell division.


Description: Graphic copy

  1. DNA damage arrests the cycle at G1 & G2, which allows time for repair before going into the S phase.
  2. At G1, damaged DNA induces the rapid synthesis of the p53 protein, which then signals cell cycle arrest.
  3. Mutations in the p53 gene are the most common genetic alterations in human cancers, illustrating the critical importance of cell cycle regulation in the life of multicellular organisms.
  4. The cell-cycle control system is based on two families of proteins: the cyclin-dependent protein kinases (Cdk) and the cyclins.
  5. Cyclins bind and activate Cdk's, which phosphorylate selected proteins on Ser/Thr residues thereby inducing downstream effector cell cycle processes.
  6. There are mitotic cyclins, which bind Cdk molecules during G2 and are required for entry during mitosis, and G1 cyclins, which binds to other Cdk molecules during G1 and are required for entry into S phase.  
  1. Regulators of Cell Cycle Progression.
    1. MPF: a Dimer of Cdc2 and Cyclin. Experiments have led to the identification of the first cell cycle regulator, M phase-promoting factor (MPF).
    2. Further studies showed that MPF could also promote the G2-to-M phase transition in mitotic cells. 
  2. Inhibitors
    1. Two families of genes, the cip/kip family (CDK interacting protein/Kinase inhibitory protein) and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) prevent the progression of the cell cycle. Because these genes are instrumental in prevention of tumor formation, they are known as tumor suppressors.
    2. The cip/kip family includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53 (which, in turn, is triggered by DNA damage e.g. due to radiation). p27 is activated by Transforming Growth Factor β (TGF β), a growth inhibitor.
    3. The INK4a/ARF family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14arf which prevents p53 degradation 
  3. Serum Tumor Markers
    1. Monoclonal antibodies are used to detect serum antigens associated with specific malignancies.
    2. These tumor markers are most useful for monitoring response to therapy and detecting early relapse.
    3. With the exception of prostate-specific antigen (PSA), tumor markers do not have sufficient sensitivity or specificity for use in screening.
    4. Cancer antigen (CA) 27.29 is used to follow response to therapy in metastatic breast cancer. Carcinoembryonic antigen is used to detect relapse of colorectal cancer.
    5. CA 19-9 may be helpful in establishing the nature of pancreatic masses.
    6. CA 125 is useful for evaluating pelvic masses in postmenopausal women, monitoring response to therapy in women with ovarian cancer, and detecting recurrence of this malignancy.
    7. Alpha-fetoprotein (AFP), a marker for hepatocellular carcinoma.
    8. Beta subunit of human chorionic gonadotropin (b-hCG) is an integral part of the diagnosis and management of gestational trophoblastic disease.
    9. Combined AFP and b-hCG testing is an essential adjunct in the evaluation and treatment of nonseminomatous germ cell tumors, and in monitoring the response to therapy.
    10. PSA is used to screen for prostate cancer and to detect recurrence of the malignancy.
    11. Conditions Associated with Elevated Tumor Marker Levels Q
      1. Tumor marker  -  CA 27.29
        1. Normal value  - <38 units per mL
        2. Primary tumor(s) - Breast cancer   
        3. Additional associated
        4. Malignancies - Colon, gastric, hepatic, lung, pancreatic, ovarian, and prostate cancers
          Benign conditions -  Breast, liver, and kidney disorders, ovarian cysts
          Level wherebenign
          Disease is unlikely - 100 units per mL
          Sensitivity - Elevated in 33%  of early-stage breast cancers and 67% of late stage breast cancers
      2. Tumor marker - CEA (Carcinoembryonic antigen;)
        1. Normal value - 2.5 ng per mL in nonsmokers <5 ng per mL in smokers
        2. Primary tumor(s) - Colorectal cancer
        3. Additional associated malignancies - Breast, lung, gastric, pancreatic, bladder, medullary thyroid, head / neck, cervical, and hepatic cancers, lymphoma,   melanoma
        4. Benign conditions - Cigarette smoking, peptic ulcer, IBD, pancreatitis, hypothyroidism, cirrhosis, biliary obstruction
        5. Level wherebenign disease is unlikely - 10 ng per mL
        6. Sensitivity - Elevated in less than 25% of early-stage colon cancers and 75% of late-stage colon cancers
      3. Tumor marker  - CA 19-9
        1. Normal value - 37 units per mL
        2. Primary tumor(s) - Pancreatic and biliary tract cancers
        3. Additional associated malignancies - Colon, esophageal, and hepatic cancers
        4. Benign conditions - Pancreatitis, biliary disease, cirrhosis
          Level wherebenign disease is unlikely - 1,000 units per mL
        5. Sensitivity  - Elevated in 80% to 90% of pancreatic cancers and 60% to 70% of biliary tract cancers
      4. Tumor marker - AFP
        1. Normal value - 5.4 ng per mL
        2. Primary tumor(s) - Hepatocellular carcinoma, nonseminomatous germ cell tumors
        3. Additional associated malignancies - Gastric, biliary, and pancreatic cancers
        4. Benign conditions - Cirrhosis, viral hepatitis, pregnancy
        5. Level wherebenign disease is unlikely - 500 ng per mL
        6. Sensitivity - Elevated in 80% of hepatocellular carcinomasNonseminomatous germ cell tumors: see b-hCG below
      5. Tumor marker - b-hCG
        1. Normal value - 5 mIU per mL
        2. Primary tumor(s) - Nonseminomatous germ cell tumors, gestational trophoblastic
        3. Additional associated malignancies - Rarely, gastrointestinal cancers
        4. Benign conditions - Hypogonadal states, marijuana use
        5. Level wherebenign disease is unlikely - 30 mIU per mL7
        6. Sensitivity - AFP or b-hCG elevated in 85% of nonseminomatous germ cell tumors; elevated in only 20% of early-stage nonseminomatous germ cell tumors
      6. Tumor marker - CA 125 (Cancer Antigen 125)
        1. Normal value - 35 units per mL
        2. Primary tumor(s) - Ovarian cancer
        3. Additional associated malignancies - Endometrial, fallopian tube, breast, lung, esophageal, gastric, hepatic, and pancreatic cancers
        4. Benign conditions - Menstruation, pregnancy, fibroids, ovarian cysts, PID, cirrhosis, ascites, pleural / pericardial effusions, endometriosis
        5. Level wherebenign disease is unlikely - 200 units per mL11
        6. Sensitivity - Elevated in about 85% of ovarian cancers; elevated in only 50% of early-stage ovarian cancers
      7. Tumor marker - PSA (prostate-specific antigen.)
        1. Normal value - 4 ng/mL for screening Undetectable level after radical prostatectomy
        2. Primary tumor(s) - Prostate cancer
        3. Additional associated malignancies - None
        4. Benign conditions - Prostatitis, benign prostatic hypertrophy, prostatic trauma, after ejaculation
        5. Level wherebenign disease is unlikely - 10 ng per mL12
        6. Sensitivity - Elevated in more than 75 percent of organ-confined prostate cancers14

AFP and b-hCG Levels in Germ Cell Tumors and Gestational Trophoblastic Disease


AFP elevation

b-hCG elevation

Seminoma and dysgerminoma


Occasional, minimal

Embryonal cell carcinoma






Yolk sac tumors






Gestational trophoblastic disease†



  1. Both AFP and b-hCG play crucial roles in the management of patients with nonseminomatous germ cell tumors.
  2. The AFP or b-hCG level is elevated in 85 percent of patients with these tumors, but in only 20 percent of patients with stage I disease. Hence, these markers have no role in screening.
  3. In patients with extragonadal disease or metastasis at the time of diagnosis, highly elevated AFP or b-hCG values can be used in place of biopsy to establish a diagnosis of nonseminomatous germ cell tumor.
  4. AFP values in excess of 10,000 ng per mL or b-hCG levels above 50,000 mIU per mL at initial diagnosis portend a poor prognosis, with a five-year survival rate of 50 percent.
  5. Similarly staged patients with lower AFP and b-hCG levels have a cure rate higher than 90 percent.
  6. Following AFP and b-hCG levels is imperative in monitoring response to treatment in patients who have nonseminomatous germ cell tumors.
  7. Patients with AFP and b-hCG levels that do not decline as expected after treatment have a significantly worse prognosis.
  8. AFP or b-hCG elevation is frequently the first evidence of germ cell tumor recurrence; a confirmed elevation should prompt reinstitution of therapy.
  9. The b-hCG level is used to diagnose gestational trophoblastic disease, a rare neoplastic complication of pregnancy.
  10. The b-hCG value is followed to assess response to treatment and to detect relapse in a manner similar to that for germ cell tumor.
  1. Oncogene
    1. An oncogene is a modified gene, or a set of nucleotides that codes for a protein, that increases the malignancy of a tumor cell.
    2. New research indicates that small RNAs 21-25 nucleotides in length called miRNAs can control expression of these genes by downregulating them.
    3. The first oncogene was discovered in 1970 and was termed SRC (pronounced SARK). Src was in fact first discovered as an oncogene in a chicken retrovirus. 
  2. Proto-oncogene
    1. A proto-oncogene is a normal gene that can become an oncogene, either after mutation or increased expression.
    2. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation.
    3. Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through its protein product.
    4. Upon activation, it (or its product) becomes a tumor inducing agent, an oncogene.
  3. Activation
    1. The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are two basic activation types:
      1. A mutation within a proto-oncogene can cause a change in the protein structure, caused by an increase in protein (enzyme) activity a loss of regulation the creation of a hybrid protein, through a chromosomal aberration during cell division.
      2. A distinct aberration in a dividing stem cell in the bone marrow leads to adult leukemia
    2. An increase in protein concentration, caused by
      1. an increase of protein expression (through misregulation)
      2. an increase of protein stability, prolonging its existence and thus its activity in the cell
      3. a gene duplication, resulting in an increased amount of protein in the cell

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