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Regulation of mTOR and cell growth in response to energy stress by REDD1

Avi Sofer1, Kui Lei, Cory M Johannessen

  • 1Massachusetts General Hospital Cancer Center and Harvard Medical School, GRJ-904, 55 Fruit Street, Boston, Massachusetts 02114, USA.

Molecular and Cellular Biology
|July 1, 2005
PubMed

Insights

The stress response gene REDD1 controls cell growth by inhibiting the mTOR pathway during energy depletion. This finding reveals REDD1 as a key regulator in the tuberous sclerosis complex-mTOR signaling pathway.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The tuberous sclerosis tumor suppressors TSC1 and TSC2 are critical regulators of the mechanistic target of rapamycin (mTOR) pathway, controlling cell growth and translation.
  • The REDD1 gene was previously identified as a mediator of TSC-dependent mTOR regulation by hypoxia.

Purpose of the Study:

  • To investigate the role of REDD1 in mediating the cellular response to energy stress through the TSC-mTOR pathway.
  • To elucidate the mechanism by which REDD1 regulates mTOR function during energy depletion.

Main Methods:

  • Utilized REDD1 knockout (REDD1-/-) cells and cells with tetracycline-inducible REDD1 expression.
  • Assessed mTOR substrate phosphorylation (S6K, 4E-BP1) following ATP depletion or AMP-activated protein kinase (AMPK) activation.
  • Investigated the interaction with the TSC1/2 complex and Rheb.
  • Measured cellular size changes in response to REDD1 modulation and rapamycin treatment.

Main Results:

  • Endogenous REDD1 is induced by energy stress, and its absence impairs mTOR substrate dephosphorylation.
  • REDD1 inhibition of mTOR requires TSC2 and is independent of AMPK, but dependent on Rheb.
  • Inducible REDD1 expression decreases cell size, while REDD1 deficiency leads to defective growth regulation under energy stress.
  • Knockdown of REDD1 increases cell size in a rapamycin-sensitive manner.

Conclusions:

  • REDD1 acts as a crucial transducer of the cellular response to energy depletion via the TSC-mTOR pathway.
  • REDD1 directly inhibits mTOR signaling to control cell growth during periods of low energy availability.
  • These findings highlight REDD1 as a key player in cellular energy homeostasis and growth control.

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