Question

A. Explain briefly why loss-of-function hedgehog and smoothened mutations yield the same phenotype but a loss-of-function patched mutation yields the opposite phenotype in flies.

B. Ski and SnoN were originally identified as oncoproteins. Explain how the constitutive expression of these proteins is cancer-promoting.

Answer 1

Answer:- (B) Constitutive Expression refers to genes that are transcribed in an ongoing manner, with control limited to that directly associated with the metabolic state of the organism.A constitutive gene is a gene that is transcribed continually as opposed to a facultative gene, which is only transcribed when needed.

The Ski protein is a nuclear oncogene that is associated with tumors at high cellular concentrations. It is expressed both inside and outside of the nucleus. Ski has been shown to interfere with normal cellular functioning by directly impeding expression of certain genes inside the nucleus of the cell. It disrupts signaling proteins that activate genes.It is in the same family as the SnoN protein. The different domains have different functions, with the primary domains interacting with Smad proteins.

Ski protein in cancerous cells acts as a suppressor, inhibiting transforming growth factor β (TGF- β) signaling. TGF- β is a protein which regulates cell growth. Signaling is regulated by a family of proteins called the Smad proteins. Ski is present in all adult and embryonic cells at low levels, however an over expression of the protein is characteristic of tumor cells.Ski has been linked to various cancers including human melanomas, esophageal squamous cell carcinoma, cervical cancer and the process of tumor progression. The link of Ski with human melanoma has been the most studied area of the protein’s link to cancer. Ski protein prevents response to TFG- β levels, causing tumor formation.The SnoN protein was similar protein. High levels of Ski protein inactivate tumor suppression by displacement of other proteins and interference with the signaling pathway of TGF- β.This has been associated with cancer due to the large number of roles that peptide growth factors, of which TGF-beta are a subfamily, play in regulating cellular functions such as cell proliferation, apoptosis and specification.

Answer:-(A) Smoothened (Smo) is a seven-pass membrane protein that is essential for all Hh signaling.The activity of Smo is repressed by the Hh-binding, multi-pass transmembrane receptor Patched (Ptc), since, in the absence of Ptc, downstream signaling events are activated by Smo in a ligand-independent manner.The binding of Hh to Ptc relieves the repression that Ptc normally exerts on Smo.Several genes of the Hh pathway were first identified in the fly Drosophila melanogaster and later in vertebrates. Many of the names of the genes involved in the Hh signaling pathway were originally descriptive of the phenotype manifested in mutant Drosophila larvae.

Loss-of-function mutations in murine Gli genes are likely to cause phenotypes differently from equivalent mutations in Hedgehog genes. In particular, even a triple knockout of the Gli1, Gli2 and Gli3 genes, will presumably behave different from combined mutations in the Sonic, Indian and Desert hedgehog genes.