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P16 and ARF: Activation of Teenage Proteins in Old Age p16 and ARF: activation of teenage proteins in old age Ande Satyanarayana, K. Lenhard Rudolph J Clin Invest. 2004;114(9):1237-1240. https://doi.org/10.1172/JCI23437. Commentary Cellular senescence induced by different stresses and telomere shortening appears to play an important role in the aging process. The products of the INK4a/ARF locus — p16INK4a and ARF — arrest cell proliferation at the senescence stage by exerting their effects on retinoblastoma protein– and p53-mediated responsive pathways. A study in this issue of the JCI provides experimental evidence of a specific upregulation of these cell cycle inhibitors in a variety of organs during mammalian aging. Find the latest version: https://jci.me/23437/pdf commentaries 21. Matheny, S.A., et al. 2004. Ras regulates assembly by ceramide-activated protein kinase. Nature. 42. Volle, D.J., et al. 1999. Phosphorylation of the of mitogenic signalling complexes through the 378:307–310. kinase suppressor of ras by associated kinases. Bio- effector protein IMP. Nature. 427:256–260. 32. Mathias, S., Dressler, K.A., and Kolesnick, R.N. chemistry. 38:5130–5137. 22. Wang, X., and Studzinski, G.P. 2001. Phos- 1991. Characterization of a ceramide-activated pro- 43. Zhou, M., Horita, D.A., Waugh, D.S., Byrd, R.A., phorylation of raf-1 by kinase suppressor of ras is tein kinase: stimulation by tumor necrosis factor and Morrison, D.K. 2002. Solution structure and inhibited by “MEK-specific” inhibitors PD 098059 alpha. Proc. Natl. Acad. Sci. U. S. A. 88:10009–10013. functional analysis of the cysteine-rich C1 domain and U0126 in differentiating HL60 cells. Exp. Cell 33. Joseph, C.K., Byun, H.S., Bittman, R., and Kolesnick, of kinase suppressor of Ras (KSR). J. Mol. Biol. Res. 268:294–300. R.N. 1993. Substrate recognition by ceramide-acti- 315:435–446. 23. Xing, H.R., and Kolesnick, R. 2001. Kinase suppres- vated protein kinase. Evidence that kinase activity 44. Muller, J., Cacace, A.M., Lyons, W.E., McGill, sor of Ras signals through Thr269 of c-Raf-1. J. Biol. is proline-directed. J. Biol. Chem. 268:20002–20006. C.B., and Morrison, D.K. 2000. Identification of Chem. 276:9733–9741. 34. Liu, J., Mathias, S., Yang, Z., and Kolesnick, R.N. B-KSR1, a novel brain-specific isoform of KSR1 24. Wang, X., and Studzinski, G.P. 2004. Kinase sup- 1994. Renaturation and tumor necrosis factor- that functions in neuronal signaling. Mol. Cell. Biol. pressor of RAS (KSR) amplifies the differentiation alpha stimulation of a 97-kDa ceramide-activated 20:5529–5539. signal provided by low concentrations 1,25-dihy- protein kinase. J. Biol. Chem. 269:3047–3052. 45. Sugimoto, T., Stewart, S., Han, M., and Guan, K.L. droxyvitamin D3. J. Cell. Physiol. 198:333–342. 35. Basu, S., Bayoumy, S., Zhang, Y., Lozano, J., and 1998. The kinase suppressor of Ras (KSR) modu- 25. 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Chem. 275:17276–17280. inhibits the activation of extracellular ligand- 47. Spitaler, M., Villunger, A., Grunicke, H., and Uber- 27. Galve-Roperh, I., et al. 2000. Anti-tumoral action of regulated (ERK) mitogen-activated protein (MAP) all, F. 2000. Unique structural and functional prop- cannabinoids: involvement of sustained ceramide kinase by growth factors, activated Ras, and Ras erties of the ATP-binding domain of atypical pro- accumulation and extracellular signal-regulated effectors. J. Biol. Chem. 273:7743–7748. tein kinase C-iota. J. Biol. Chem. 275:33289–33296. kinase activation. Nat. Med. 6:313–319. 38. Cacace, A.M., et al. 1999. Identification of consti- 48. Tsakraklides, V., and Solomon, M.J. 2002. Compar- 28. Grassme, H., Schwarz, H., and Gulbins, E. 2001. tutive and ras-inducible phosphorylation sites of ison of Cak1p-like cyclin-dependent kinase-activat- Molecular mechanisms of ceramide-mediated KSR: implications for 14-3-3 binding, mitogen- ing kinases. J. Biol. 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Hypothesis: ceramide pressor of Ras1 prevents oncogenic ras signaling in threonine protein kinase lacking the catalytic lysine conditionally activates atypical protein kinases C, mice. Cancer Res. 63:4232–4238. in subdomain II. J. Biol. Chem. 275:16795–16801. Raf-1 and KSR through binding to their cysteine- 41. Michaud, N.R., et al. 1997. KSR stimulates Raf-1 52. Verissimo, F., and Jordan, P. 2001. WNK kinases, rich domains. Biochem. J. 331:679–680. activity in a kinase-independent manner. Proc. Natl. a novel protein kinase subfamily in multi-cellular 31. Yao, B., et al. 1995. Phosphorylation of Raf Acad. Sci. U. S. A. 94:12792–12796. organisms. Oncogene. 20:5562–5569. p16 and ARF: activation of teenage proteins in old age Ande Satyanarayana and K. Lenhard Rudolph Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany. Cellular senescence induced by different stresses and telomere shorten- cence checkpoint is also considered to be a ing appears to play an important role in the aging process. The products of major mechanism for suppressing tumors, the INK4a/ARF locus — p16INK4a and ARF — arrest cell proliferation at the protecting the organism from cancer dur- senescence stage by exerting their effects on retinoblastoma protein– and ing early life (2). A number of stimuli have p53-mediated responsive pathways. A study in this issue of the JCI provides been identified as inducing senescence, experimental evidence of a specific upregulation of these cell cycle inhibi- and these include telomere shortening tors in a variety of organs during mammalian aging (see the related article (3), DNA damage (4), oxidative stress (5), beginning on page 1299). sustained mitogen stimulation (6), and other cellular stresses. Senescence induced According to a current hypothesis on by telomere shortening has been called Nonstandard abbreviations used: CDK, cyclin-depen- dent kinase; CDKI, CDK inhibitor; CR, caloric restric- aging, senescent cells accumulate in the “replicative senescence” and is a result of tion; GH, growth hormone; GHR, GH receptor; MDM2, organism, and this results in failure of DNA damage–like signals generated by mouse double minute 2; pRB, retinoblastoma protein; organ homeostasis and function (1). Cel- dysfunctional telomeres (3, 4). In addition SA- -gal, senescence-associated -galactosidase. β β lular senescence — characterized by the to telomere attrition, several other mecha- Conflict of interest: The authors have declared that no conflict of interest exists. permanent arrest of cell proliferation — is nisms can abruptly induce senescence Citation for this article: J. Clin. Invest. 114:1237–1240 detrimental to the regenerative capacity of independent of telomere length, termed (2004). doi:10.1172/JCI200423437. organs during aging. However, the senes- “premature senescence,” including: over- The Journal of Clinical Investigation http://www.jci.org Volume 114 Number 9 November 2004 1237 commentaries Figure 1 Illustration showing possible mechanisms of p16INK4a and ARF induction and the role of these proteins in aging. The accumulation of persistent and increasing DNA damage in senescent cells in response to telomere shortening, DNA damage, inappropriate activation of signaling pathways, and production of ROS during aging results in transcriptional activation of the INK4a/ARF locus. Mitogen stimulation may amplify the signals of DNA damage. Alternative stochastic mechanisms of aging that lead to p16INK4a/ARF induction might also exist. Upregulation of p16INK4a and ARF activates pRB and p53 pathways, which in turn lead to cell cycle arrest and regenerative defects. In addition, p16INK4a/ARF upregulation might influence cellular functions in mitotically inactive organs during aging. Cyc D, cyclin D; BMI1, B lymphoma Mo-MLV insertion region; ID1, inhibitor of DNA binding 1; ETS1, v-ets erythroblastosis virus E26 oncogene homolog 1. activation of mitogenic pathways, such as p14ARF (murine p19ARF), p15INK4b, and hypophosphorylated and growth-suppres- INK4c Ras, Raf, or MEK, or overexpression of E2F p18 — all of which have a role in cell sive state and induces G1 cell cycle arrest or v-ets erythroblastosis virus E26 onco- cycle regulation (10).
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