Question

The protein mTOR is observed to be overactive in many cancers. Explain why this is the case. Name three events that cause mTORC1 to become activated, three events that cause mTORC1 to become inactivated, and explain the molecular signals that lead to each outcome

Answer 1

Details of the answers given in explanations.

Step-by-step explanation:

mTOR is a serine/threonine protein kinase that regulates cell growth, proliferation, survival, protein synthesis and transcription. It stands for mechanistic Target Of Rapamycin.

Over-activation of mTOR signaling can contribute to development of tumors. There are several reasons for constitutive activation of mTOR.

1- Mutations in tumor suppressor PTEN gene: PTEN phosphatase negatively affects mTOR signalling through interfering with the effect of PI3K, an upstream effector of mTOR. So mutation that inactivates PTEN phosphatase can lead to over-activation of mTOR

2- Increasing mTOR activity drives cell cycle progression and increases cell.

3- Prevention of Autophagy of the defective cells: Active mTOR supports tumor growth also indirectly by inhibiting autophagy. Constitutively activated mTOR supplies cells with oxygen and nutrients by increasing the translation of HIF1A (Hypoxia-Inducible Factor 1A) and supporting angiogenesis.

Three events that can lead to the activaton of mTOR are:

1- Mutations in tumor suppressor PTEN gene: PTEN phosphatase negatively affects mTOR signalling through interfering with the effect of PI3K, an upstream effector of mTOR. So mutation that inactivates PTEN phosphatase can lead to over-activation of mTOR.

2- mTOR can be activated by the growth hormones like Insulin or Growth hormones that bind to the receptor & allow PI3K through a Ras kinase activate mTOR.

3- Mutations in RHEB protein (a Ras kinase) also leads to over-activation of the mTOR protein as it regulates the mTOR pathway by inactivation of the mTOR protein.

Also, mutations in tumor sclerosis complex (TSC1 or TSC2) can also lead to over-activation of mTOR and causes unregulated cell proliferation.

Inhibition of the mTOR can occur via:

1- Rapamycin inhibits mTOR; this appears to control unregulated proliferation of cells seen in cancer.

2- A primary way that mTOR exerts its regulatory effects on cell proliferation is by controlling the production of cyclin D1. Inhibition of the activity of the Cdk-cyclin D1 cmplex can lead to inhibition of tumerogenesis due to mTOR.

3- TSC1/TSC2 complex participates in the inhibition of the mTOR pathway by inhibiting RHEB (the Ras kinase which activates mTOR).