Telomeres and telomerase in adrenocortical tissue maintenance, carcinogenesis, and aging

1. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 1

   Model of telomere shortening and telomerase activity. (A) Telomere shortening. A 3′-overhang is created by the lagging strand synthesis after excision of the RNA primer resulting in a shortened telomere. 3′-synthesis of the leading strand can be carried to completion by the DNA polymerase. A 3′-overhang is created by a yet unidentified mechanism, most likely a 5′-exonuclease. After a certain number of cell divisions, telomeres become critically short and induce cellular senescence or apoptosis. (B) Telomere maintenance. Telomerase, consisting of the protein (TERT) and RNA (TERC) subunit extend telomeres by adding telomeric repeats (TTAGGG) in the 3′-direction. The DNA polymerase can then synthesize the lagging strand. This process can maintain telomere length or lead to telomere lengthening.
2. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 2

   (A) Multiple shelterin complexes can be found at the telomere DNA T-loop and most likely exist in different compositions to serve the multiple functions of the telomere, protect it from recognition and processing by the DNA surveillance machinery. (B) Model of the telomere cap complex (shelterin complex) bound to the end of the telomere. (C) Data from a gene expression array (IDs refer to the HG-U133 Plus 2 array) of adrenocortical tumors. Fold change is expressed as ACC versus ACA and NL as one group. TERT, POT1, TPP1/ACD, and TIN2 are significantly differently expressed in malignant versus non-malignant adrenocortial tissues. Official gene symbols are used in the array: POT1, protection of telomeres 1; ACD, adrenocortical dysplasia homologue (TPP1/ACD); TERT, telomerase reverse transcriptase; TERF2IP, TERF2-interacting protein (RAP1); TERF2, telomeric repeat-binding factor 2 (TRF2); TERF1, telomeric repeat-binding factor 1 (TRF1); TINF2, TRF1-interacting nuclear factor 2 (TIN2).
3. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 3

   Model of genomic shuffling by breakage fusion bridge (BFB) cycles. Dysfunctional telomeres (absent red circles) fuse and form dicentric chromosomes. During cell division, the fused chromosomes are pulled to the two different poles of the emerging daughter cells. During anaphase these can be observed as anaphase bridges, chromosomal material spanning from one daughter cell to the other. Eventually, a break occurs and creates another open end, which can serve as a new starting point for a subsequent BFB. Ultimately, this process leads to genomic amplifications and deletions.
4. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 4

   Telomere-focused model of tumorigenesis. Dysfunctional telomeres, either as a consequence of telomere decapping or resulting from telomere shortening, will be recognized by the DNA surveillance machinery and induce senescence or apoptosis (telomeres are shown as red circles). In the setting of checkpoint deficiency, such as p53 deficiency, chromosomes may fuse and start BFBs, leading to a shuffling of the genome and genomic amplifications and deletions. This first step generates a pro-cancer genome. In a second step, chromosomes are stabilized by telomere length maintenance mechanisms (either TA or ALT) and the emerging cancer cells acquire independence of telomere shortening-induced senescence or apoptosis.
5. View larger version:

   • In this window
   • In a new window

   • Download as PowerPoint Slide

   Figure 5

   Proposed model of the aging adrenal cortex. This hypothesis links cellular aging/senescence to organ and organismal aging. The proposed stem cell compartment of the adrenal cortex (yellow circles) can be found in the periphery of the gland. As the normal adult adrenal cortex does not have any telomere length maintenance mechanisms, telomeres shorten over time and multiple cell cycles and lead to cellular senescence in the stem cell compartment (green circles). In the setting of a diminished stem cell pool, the vital functions of glucocorticoid and mineralocorticoid production in the zona glomerulosa and fasciculata are ensured at the expense of the zona reticularis (orange zone). This results in decreased DHEA/DHEAS secretion and may ultimately relay cellular aging, induced by telomere shortening, via organ aging to aging of the organism.

• © 2009 Society for Endocrinology